RAF1

General Information

Full gene name:v-raf-1 murine leukemia viral oncogene homolog 1 Entrez Gene ID:5894 Location:3p25 Synonyms:Raf-1, CRAF, c-Raf, NS5 Type:protein-coding

User SNPs

SNPs given by the user that are near or inside this gene:

SNP	Distance (bp)	Direction
rs1801282	231975	downstream

NCBI Summary

This gene is the cellular homolog of viral raf gene (v-raf). The encoded protein is a MAP kinase kinase kinase (MAP3K), which functions downstream of the Ras family of membrane associated GTPases to which it binds directly. Once activated, the cellular RAF1 protein can phosphorylate to activate the dual specificity protein kinases MEK1 and MEK2, which in turn phosphorylate to activate the serine/threonine specific protein kinases, ERK1 and ERK2. Activated ERKs are pleiotropic effectors of cell physiology and play an important role in the control of gene expression involved in the cell division cycle, apoptosis, cell differentiation and cell migration. Mutations in this gene are associated with Noonan syndrome 5 and LEOPARD syndrome 2. [provided by RefSeq, Jul 2008]

OMIM

OMIM ID:`OMIM ID 164760 `_

Allelic Variants (Selected Examples)

.0001 NOONAN SYNDROME 5

In 7 unrelated patients with Noonan syndrome (NS5; 611553) and 1 patient with LEOPARD syndrome-2 (611554), Pandit et al. (2007) identified heterozygosity for a 770C-T transition in exon 7 of the RAF1 gene, resulting in a ser257-to-leu (S257L) substitution at a conserved residue in the CR2 domain. All patients had hypertrophic cardiomyopathy (CMH), including a 3.6-year-old girl with CMH at birth and a 35-year-old woman with LEOPARD syndrome. Ectopically expressed S257L mutants demonstrated increased kinase activity and enhanced ERK (see 176948) activation.

Razzaque et al. (2007) identified the S257L mutation of the RAF1 gene in 4 unrelated patients with Noonan syndrome, 3 with obstructive and 1 with nonobstructive CMH. The mutation was not found in 100 control individuals or in 100 patients with CMH without Noonan syndrome.

.0002 NOONAN SYNDROME 5

In 5 affected individuals of 2 unrelated families with Noonan syndrome (NS5; 611553), Pandit et al. (2007) identified heterozygosity for a 781C-T transition in exon 7 of the RAF1 gene, resulting in a pro261-to-ser (P261S) substitution at a conserved residue in the CR2 domain. Four of the 5 patients had hypertrophic cardiomyopathy (CMH); the 1 individual with a P261S change but without CMH was a 6-year-old girl whose 38-year-old mother had the same mutation and had been diagnosed with CMH at 23 years of age. The mutation was not found in 210 control individuals.

Razzaque et al. (2007) identified the P261S mutation in 3 Noonan syndrome patients, a 1-year-old boy and his 33-year-old father and an unrelated 16-year-old boy. All 3 displayed CMH. The mutation was not found in 100 control individuals or in 100 individuals with CMH without Noonan syndrome. Transfection studies in HEK293 cells demonstrated that P261S behaved as a gain-of-function mutant with increased kinase and ERK (see 176948) activation compared with wildtype RAF1.

.0003 NOONAN SYNDROME 5

In a sister and brother with Noonan syndrome (NS5; 611553), Pandit et al. (2007) identified heterozygosity for a 1472C-G transversion in exon 14 of the RAF1 gene, resulting in a thr491-to-arg (T491R) substitution in the CR3 domain. Neither sib had hypertrophic cardiomyopathy. The mutation was not found in 210 control individuals.

.0004 LEOPARD SYNDROME 2

In a 43-year-old woman with LEOPARD syndrome-2 (611554), Pandit et al. (2007) identified an 1837C-G transversion in exon 17 of the RAF1 gene, resulting in a leu613-to-val (L613V) substitution at a conserved residue in the C terminus. The patient had hypertrophic cardiomyopathy.

Razzaque et al. (2007) identified the L613V mutation, which they designated as being located in the CR3 domain of RAF1, in 2 unrelated boys with Noonan syndrome (NS5; 611553), neither of whom had hypertrophic cardiomyopathy. The mutation was not found in 100 control individuals or in 100 patients with hypertrophic cardiomyopathy without Noonan syndrome. Transfection studies in HEK293 cells demonstrated that L613V behaved as a gain-of-function mutant with increased kinase and ERK (see 176948) activation compared with wildtype RAF1.

NCBI Phenotypes

• Gene Reviews
• Hypertrophy-associated polymorphisms ascertained in a founder cohort applied to heart failure risk and mortality.
• Noonan syndrome 5
• OMIM
• Biological, clinical and population relevance of 95 loci for blood lipids.
• GTR
• LEOPARD syndrome 2
• NHGRI GWA Catalog

Gene Ontology

• fibroblast growth factor receptor signaling pathway
• pseudopodium
• cytosol
• cytoplasm
• protein heterodimerization activity
• identical protein binding
• response to hypoxia
• axon guidance
• negative regulation of cell proliferation
• plasma membrane
• regulation of apoptotic process
• mitochondrial outer membrane
• negative regulation of apoptotic process
• cell proliferation
• protein binding
• nerve growth factor receptor signaling pathway
• MAPK cascade
• protein kinase activity
• epidermal growth factor receptor signaling pathway
• negative regulation of cysteine-type endopeptidase activity involved in apoptotic process
• metal ion binding
• heart development
• ATP binding
• activation of adenylate cyclase activity
• Ras GTPase binding
• insoluble fraction
• nucleus
• regulation of cell motility
• platelet activation
• small GTPase mediated signal transduction
• cytoskeleton organization
• positive regulation of peptidyl-serine phosphorylation
• wound healing
• protein phosphorylation
• activation of MAPKK activity
• signal transduction
• Ras protein signal transduction
• apoptotic process
• mitogen-activated protein kinase kinase binding
• negative regulation of protein complex assembly
• insulin receptor signaling pathway
• synaptic transmission
• regulation of Rho protein signal transduction
• MAP kinase kinase kinase activity
• blood coagulation
• protein serine/threonine kinase activity
• regulation of cell differentiation

KEGG Pathways

• VEGF signaling pathway
• Melanoma
• Bladder cancer
• Acute myeloid leukemia
• GnRH signaling pathway
• Influenza A
• ErbB signaling pathway
• Focal adhesion
• Long-term potentiation
• Fc epsilon RI signaling pathway
• Melanogenesis
• Chronic myeloid leukemia
• Alcoholism
• B cell receptor signaling pathway
• Colorectal cancer
• Regulation of actin cytoskeleton
• Vascular smooth muscle contraction
• Neurotrophin signaling pathway
• Natural killer cell mediated cytotoxicity
• Tuberculosis
• Endometrial cancer
• ``Insulin` signaling pathway <http://www.genome.jp/dbget-bin/show_pathway?hsa04910+5894>`_
• T cell receptor signaling pathway
• Serotonergic synapse
• Long-term depression
• Pathways in cancer
• Hepatitis C
• Chemokine signaling pathway
• Fc gamma R-mediated phagocytosis
• Prostate cancer
• Gap junction
• Glioma
• MAPK signaling pathway
• Renal cell carcinoma
• Non-small cell lung cancer
• Pancreatic cancer
• Progesterone-mediated oocyte maturation

GeneRIFs

• These findings support a role of Slug in mediating Raf 1-induced transcriptional repression of occludin and subsequent epithelial to mesenchymal transition. [PMID 16924233]
• data suggest that Raf-1 is the predominant Raf isoform responsible for regulating cellular growth in ovarian cancer cells and may be particularly important in high grade serous ovarian cancers [PMID 16332724]
• DGKeta acts as a novel critical regulatory component of the Ras/B-Raf/C-Raf/MEK/ERK signaling cascade via a previously unidentified mechanism. [PMID 19710016]
• Data show that bilirubin interacts with the Raf/ERK/MAPK pathway, effect on cyclin D1 and Raf content, altered retinoblastoma protein profile of hypophosphorylation, calcium influx, and YY1 proteolysis. [PMID 22262839]
• effects of paclitaxel on Raf-1 phosphorylation in ovarian cancer cells [PMID 12087097]
• Hepatitis B virus could up-regulate Raf1 expression by enhancing the activity of its promoter in a dose-dependent manner, and HBs and HBx may be involved in this process. [PMID 21207082]
• Findings suggest that modulating the C-RAFSer(259)/14-3-3 protein-protein interaction with a stabilizing small molecule may yield a novel potential approach for treatment of diseases resulting from an overactive Ras-RAF-MAPK pathway. [PMID 20679480]
• These findings support the thesis that Raf-1 signals cell proliferation and cell differentiation through different intermediary proteins. [PMID 16883571]
• together, our data suggest that the synergistic activation of Raf-1 kinase in response to PMA and H(2)O(2) occurs via mechanisms that involve an interaction of Raf-1 kinase and PKC-epsilon. [PMID 14623285]
• Pak1-dependent Raf-1 phosphorylation regulates its mitochondrial localization, phosphorylation of BAD, and Bcl-2 association [PMID 15849194]
• Rheb has a central role in the regulation of the Ras/B-Raf/C-Raf/MEK signaling network [PMID 16803888]
• Affinity Capture-Western; Reconstituted Complex; Two-hybrid [PMID 16803888]
• Based on our results, it is possible that a subtle dysfunction (expression) of the RAF1 gene is involved in the development of the most common male reproductive tract disorder - unilateral or bilateral cryptorchidism [PMID 20389169]
• This work provides new insight into how the cell microenvironment may influence Raf-1 expression to modulate cell-Fibronectin interactions in 3D. [PMID 16707572]
• analysis of molecular pertubations allowing dysplasia to progress further to adenocarcinoma induced by exaggerted c-Raf kinase activity [PMID 19812696]
• Affinity Capture-Western [PMID 12237340]
• 14-3-3-epsilon interacts with Raf-1. [PMID 7644510]
• Affinity Capture-Western; Reconstituted Complex; Two-hybrid [PMID 12620389]
• Two-hybrid [PMID 12620389]
• Two-hybrid [PMID 12620389]
• Two-hybrid [PMID 12620389]
• C-RAF interacts with SGN3. [PMID 12620389]
• C-RAF interacts with CPS1. [PMID 12620389]
• C-RAF interacts with CCT3. [PMID 12620389]
• C-RAF interacts with TIMM50. [PMID 12620389]
• C-RAF interacts with OIP5. [PMID 12620389]
• C-RAF interacts with 14-3-3-beta. [PMID 12620389]
• C-RAF interacts with Ha-Ras. [PMID 12620389]
• C-RAF interacts with PyK. [PMID 12620389]
• RAF1 (C-Raf) interacts with RRAS2 (R-Ras). [PMID 12620389]
• RAF1 (C-Raf) interacts with CPS1. [PMID 12620389]
• RAF1 (C-Raf) interacts with PBK (TOPK). [PMID 12620389]
• RAF1 (C-Raf) interacts with COPS3 (SGN3). [PMID 12620389]
• RAF1 (C-Raf) interacts with NUDT14 (hA21). [PMID 12620389]
• RAF1 (C-Raf) interacts with an unspecified isoform of EFEMP1 (FBNL). [PMID 12620389]
• RAF1 (C-Raf) interacts with CCT3 (hC87). [PMID 12620389]
• RAF1 (C-Raf) interacts with TIMM50 (hC22). [PMID 12620389]
• RAF1 (C-Raf) interacts with PKM2 (PyK). [PMID 12620389]
• RAF1 (C-Raf) interacts with OIP5 (hC73). [PMID 12620389]
• RAF1 (C-Raf) interacts with HRAS (Ha-Ras). [PMID 12620389]
• RAF1 (C-Raf) interacts with YWHAB (14-3-3-beta). [PMID 12620389]
• c-Raf plays a unique role in mediating K-Ras signaling in non-small cell lung carcinoma and makes it a suitable target for therapeutic intervention. [PMID 21514245]
• Noonan syndrome (NS) is an autosomal dominant disorder caused by mutations in several proteins, including RAF1, which may later involve tumor onsets. [PMID 19953625]
• Raf1 potentiates drug-stimulated cyclic AMP accumulation in cells expressing adenyl cyclcase 6 after activation of multiple signaling pathways. [PMID 15470083]
• inhibition of Raf-1 using an antisense raf oligonucleotide (AS-raf-ODN) to identify downstream targets of Raf-1 using microarray gene expression analysis [PMID 16465392]
• intracellular generation of NO* by nNOS leads to S-nitrosylation of H-Ras, which interferes with Raf-1 activation and propagation of signalling through ERK1/2 [PMID 16569214]
• cAMP suppresses CRAF in melanocytes. This suppresses the oncogenic potential of CRAF. When RAS is mutated in melanoma, the cells switch their signaling from BRAF to CRAF, dysregulating cAMP signaling &amp; allowing CRAF to signal to MEK. [PMID 17018604]
• Data show that RAF not only neutralizes BAD’s pro-apoptotic activity but activates it for a new function as a pore. [PMID 19895838]
• Observational study of gene-disease association and gene-environment interaction. (HuGE Navigator) [PMID 21048031]
• Leukotriene B(4) BLT receptor signaling regulates the level and stability of cyclooxygenase-2 (COX-2) mRNA through restricted activation of Ras/Raf/ERK/p42 AUF1 pathway [PMID 20489206]
• Affinity Capture-Western [PMID 20159553]
• Affinity Capture-Western [PMID 12774123]
• mutation analysis of the conserved regions in the RAF1 gene in human colorectal adenocarcinoma [PMID 14688025]
• B-RAF interacts with C-RAF. This interaction was modelled on a demonstrated interaction between human B-RAF and monkey C-RAF . [PMID 15035987]
• Reconstituted Complex [PMID 7782277]
• Affinity Capture-Western [PMID 7782277]
• Biochemical Activity [PMID 11676916]
• Coll I activates the ERK/MAP Kinase pathway in Jurkat T cells through the activation of Ras and Raf-1. [PMID 16266749]
• The interaction between eEF-1A and C-Raf increases eEF-1A stability and induces a survival activity. [PMID 17332776]
• Affinity Capture-Western; Co-localization [PMID 17332776]
• CRAF is required for mitotic progression. Phospho-Ser338 CRAF is upregulated in mitosis and localizes to the mitotic spindles in human cell lines and tumor biopsies. [PMID 22081024]
• activated Ras, Golgi apparatus-localized Lck is needed for the full activation of Raf-1 [PMID 17998336]
• Reduction in Raf-1 kinase inhibitory protein expression in gallbladder carcinoma contributes to invasion and metastasis and is a significant prognostic marker in patients with gallbladder carcinoma. [PMID 20688353]
• Despite the effects of constitutively active Raf on pro-B cell expansion in Raf transgenic mice, Raf activation is not sufficient to rescue early B cell development in IL-7 receptor-deficient mice. [PMID 15067053]
• Data show that in hypoxic conditions or coexpressed with a constitutively active form of HIF-1alpha, c-Kit mutants activate the Ras/Raf/Mek/Erk pathway, stimulate proliferation and transform melanocytes. [PMID 19802003]
• Affinity Capture-Western; Biochemical Activity; Reconstituted Complex [PMID 11733498]
• phosphatidate promotes ERK phosphorylation in intact cells but does not activate Raf in vitro [PMID 18952605]
• Reconstituted Complex [PMID 9261098]
• Data show that in the presence of negative feedback, changes in the rate of Ras-c-Raf binding have little effect on ERK activation. [PMID 19638615]
• Conditional expression of oncogenic C-RAF in mouse pulmonary epithelial cells reveals differential tumorigenesis and induction of autophagy leading to tumor regression. [PMID 22131876]
• Nicotine induces cell proliferation by beta-arrestin-mediated activation of the Src and Rb-Raf-1 pathways om ;img camcer. [PMID 16862215]
• Study demonstrates that human TAP-1 regulates signaling in vertebrate cells, acting at a previously uncharacterized step of the Ras pathway by inhibiting the ability of Raf to translocate to activated Ras at the cell membrane. [PMID 20230813]
• proteomic analysis of Raf-1 signaling complexes was used to show that Raf-1 counteracts apoptosis by suppressing the activation of mammalian sterile 20-like kinase (MST2) [PMID 15618521]
• Raf-1 interacts with Hsp90. This interaction was modeled on a demonstrated interaction between human Raf-1 and monkey Hsp90. [PMID 15618521]
• Raf-1 interacts with MST2. This interaction was modeled on a demonstrated interaction between human Raf-1 and monkey MST2. [PMID 15618521]
• results show that raf-1 protein induction suppresses neuroendocrine marker and hormone production in human gastrointestinal carcinoid cells via a pathway dependent on MEK activation [PMID 12851216]
• Affinity Capture-Western; Reconstituted Complex [PMID 10620507]
• The state of activation of components of mTOR, Ras/Raf kinase/ERK, and nuclear factor (NF)-kappaB signal transduction pathways, as well as cell cycle protein analyte correlates in gastric adenocarcinoma cases, was examined. [PMID 18715846]
• Affinity Capture-Western [PMID 11969417]
• Affinity Capture-MS; Reconstituted Complex [PMID 17314511]
• Data show that melanoma cells expressing B-Raf(V600E) display a reduced C-Raf:B-Raf ratio, and further suppression of C-Raf increases MAPK activation and proliferation. [PMID 19917255]
• Affinity Capture-Western; Reconstituted Complex [PMID 10757792]
• Reconstituted Complex [PMID 15075335]
• Affinity Capture-Western; Reconstituted Complex [PMID 7517401]
• Affinity Capture-Western; Reconstituted Complex [PMID 7517401]
• Results indicate that the Shoc2 scaffold protein modulates Ras-dependent Raf1 activation in a Ca(2+)- and calmodulin-dependent manner. [PMID 20071468]
• dectin-1 activates two independent signaling pathways, one through Syk and one through Raf-1, to induce immune responses. [PMID 19122653]
• Affinity Capture-Western; Biochemical Activity [PMID 10576742]
• findings identify MEK/ERK as a new signaling pathway activated by NPM/ALK and indicate that the pathway represents a novel therapeutic target in the ALK-induced malignancies [PMID 16909118]
• Affinity Capture-Western; Reconstituted Complex; Two-hybrid [PMID 15854902]
• RAF interacts with Rheb. [PMID 15854902]
• Raf activation increased the expression of cyclin A, cyclin D, cyclin E, and p21(Cip1), which are associated with G(1) progression [PMID 12429936]
• Affinity Capture-Western [PMID 20039095]
• Downregulation of RKIP increased the level of free Raf-1 and thereby elevated the mitochondrial translocation of Raf-1 during HBx-mediated hepatocarcinogenesis. [PMID 21617351]
• Report cooperative effects of Akt-1 and Raf-1 on the induction of cellular senescence in doxorubicin or tamoxifen treated breast cancer cells. [PMID 21881167]
• Affinity Capture-MS; Affinity Capture-Western; Reconstituted Complex [PMID 17353931]
• Affinity Capture-MS; Affinity Capture-Western [PMID 17353931]
• Two-hybrid [PMID 11306563]
• Affinity Capture-Western [PMID 11585916]
• a functional phosphatidate binding site is necessary for Raf-1 function in embryonic development [PMID 12925535]
• Reconstituted Complex [PMID 19953087]
• Erbin has a regulatory role in the Ras-Raf-MEK pathway and may inhibit ERK activation by disrupting the Sur-8-Ras/Raf interaction [PMID 16301319]
• Results suggest that RAGE, NOX, and H-Ras/Raf-1 are implicated in the up-regulation of HSF1 or PAI-1 in vascular EC under diabetes-associated metabolic stress. [PMID 20630999]
• A pathway comprising PKCs&gt;Raf-1&gt;MEK-1&gt;ERK-1/-2 mediates the effect of gastrin on the CgA promoter, and strongly suggests that enhanced phosphorylation of Sp1 and CREB is crucial for CgA transactivation through the G protein-coupled CCK-B/gastrin receptor. [PMID 17889508]
• Two-hybrid [PMID 10848612]
• Merlin and MLK3 can interact in situ and merlin can disrupt the interactions between B-Raf and Raf-1 or those between MLK3 and either B-Raf or Raf-1. [PMID 16537381]
• Affinity Capture-Western; Reconstituted Complex [PMID 11427728]
• findings implicate Raf-1 as a pivotal regulator of endothelial cell survival during angiogenesis [PMID 12843393]
• amplification of Raf1, MEK/MAPK oncogenic signaling during tumor growth promotes the genesis of metastatic lesions from primary tumors by activating the mesenchymal epithelial transition. [PMID 22447278]
• Data show T117/T384 as Akt phosphorylation sites in MST2, and mutation of these sites inhibited MST2 binding to Raf-1 but enhanced binding to RASSF1A, accentuating downstream c-jun N-Terminal Kinase and p38 MAPK signaling and promoting apoptosis. [PMID 20086174]
• Study identified 5 mutations in RAF1 in 10 individuals with Noonan syndrome; those with mutations causing changes in the CR2 domain of RAF1 had hypertrophic cardiomyopathy, while those with mutations leading to changes in the CR3 domain did not. [PMID 17603482]
• selective reduction in catalytic activity and expression of B-Raf but not Raf-1 suggest that B-Raf may be playing an important role in altered ERK signaling in brain of suicide subjects, and thus in the pathophysiology of suicide [PMID 16172610]
• These data suggest that GILZ contributes, through protein-to-protein interaction with Raf-1 and the consequent inhibition of Raf-MEK-ERK activation, to regulating the MAPK pathway and to providing a further mechanism underlying GCH immunosuppression. [PMID 12391160]
• Affinity Capture-Western; Reconstituted Complex [PMID 12391160]
• C-RAF is the only isoform that directly binds mitochondria [PMID 18356164]
• Affinity Capture-Western; Reconstituted Complex; Two-hybrid [PMID 22222486]
• Role for caspase-9 mediated cleavage of Raf-1 in the negative feedback regulation of hematopoietic cell apoptosis induced by growth factor withdrawal. [PMID 15674327]
• Raf-1 interacts with CASP9 dimer. [PMID 15674327]
• Affinity Capture-Western; Reconstituted Complex [PMID 10531364]
• Results identify a nuclear redistribution of Raf1 during the retinoic acid-induced differentiation of HL-60 cells. [PMID 19298812]
• Affinity Capture-Western [PMID 11350735]
• reveal a paradigm of spatial regulation of Raf kinase by RKTG via sequestrating Raf-1 to the Golgi apparatus and thereby inhibiting the ERK signaling pathway [PMID 17724343]
• Targeting NRAS alone or both BRAF and CRAF in combination or both BRAF and PIK3CA together showed delay in tumor growth. [PMID 19492075]
• Affinity Capture-Western [PMID 20947508]
• Raf is regulated through phosphorylation and N terminus-C terminus interaction [PMID 12865432]
• loss of RKIP is a functional somatic event in carriers of C-RAF germline mutations, which contributes to the development of t-AML [PMID 19357705]
• Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549:BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma. [PMID 19363522]
• Raf1 may have a role in antineoplastic drug resistance [PMID 12691824]
• in human airway smooth muscle cells: TNF-alpha transactivation of the EGF receptor, with subsequent raf-1 kinase-mediated activation of adenylyl cyclase are two linked signaling pathways [PMID 17277048]
• Affinity Capture-Western [PMID 12079506]
• Infection with Chlamydia trachomatis led to the Akt-dependent, increased phosphorylation (and inactivation) of Raf-1 at serine-259. [PMID 20234004]
• Hepatitis B virus X protein stimulates the mitochondrial translocation of Raf-1 via oxidative stress [PMID 17428866]
• MEK1 interacts with and is phosphorylated by Raf-1. This interaction was modeled on a demonstrated interaction between human MEK1 and Raf-1 from an unspecified species. [PMID 15866172]
• Data suggest that Raf-1 may interfere with the role of Rad24 by competing with Rad24 for binding to Cdc25 or a direct phosphorylation of Cdc25, bypassing the checkpoint pathway in DNA repair through Cdc25 activation. [PMID 17243098]
• Loss-of-function RKIP mutants still appear to bind to Raf-1. However the stability of the complexes formed between mutants and the N-region Raf-1 phosphopeptide were drastically reduced. [PMID 18294816]
• RAF1 (RAF) interacts with GTP-HRAS (GTP-RAS). [PMID 15688026]
• Affinity Capture-Western [PMID 8084603]
• Reconstituted Complex [PMID 10498616]
• CD44 interaction with LARG and EGFR plays a pivotal role in Rho/Ras co-activation, PLC epsilon-Ca2+ signaling, and Raf/ERK up-regulation required for CaMKII-mediated cytoskeleton function and in head and neck squamous cell carcinoma progression [PMID 16565089]
• c-Raf1 activation occurs without serine 338 phosphorylation [PMID 12626521]
• GILZ1 and SGK1 provide a physical and functional link between the PI3K- and Raf-1-dependent signaling modules [PMID 19380724]
• Phosphorylation of S621 turns over rapidly and is enriched in the activated pool of endogenous Raf-1. [PMID 19595761]
• c-Raf interacts with MEK1 and activates MEK1 by phosphorylation. [PMID 8621729]
• MEK1 interacts with c-Raf [PMID 8621729]
• Data suggest that B-RAF activates C-RAF through a mechanism involving 14-3-3 mediated heterooligomerization and C-RAF transphosphorylation. [PMID 16364920]
• hPEBP4 interacts with Raf-1. This interaction was modeled on a demonstrated interaction between human hPEBP4 and mouse Raf-1. [PMID 15302887]
• Raf interacts with and phosphorylates Mek1 [PMID 14724641]
• Raf interacts with Mek2. [PMID 14724641]
• findings indicate that ligation of retinol to a specific site embedded in the regulatory domain is an important feature of c-Raf regulation in the redox pathway. [PMID 15591313]
• The results suggest that multiple cellular signaling pathways can reactivate the virus in a genetically homogeneous cell population. Further analysis revealed that the Raf/MEK/ERK/Ets-1 pathway mediates Ras-induced reactivation. [PMID 17397260]
• These data show an unexpected role of XIAP and cellular-inhibitor of apoptosis proteins in the turnover of C-RAF protein, thereby modulating the MAPK signalling pathway and cell migration. [PMID 19011619]
• Affinity Capture-Western; Reconstituted Complex [PMID 19011619]
• Affinity Capture-Western [PMID 19011619]
• Reconstituted Complex [PMID 19011619]
• Reconstituted Complex [PMID 19011619]
• the HER2/Raf-1/AP-1 axis may promote the development of androgen insensitive prostate cancer, leading to early relapse [PMID 15666389]
• PAK1 primes MEK1 for phosphorylation by Raf-1 kinase during cross-cascade activation of the ERK pathway. [PMID 11948406]
• The Raf kinase inhibitory protein (RKIP) binds to Raf-1 interfering with binding of the MEK substrate and potentially also Raf-1 activation. [PMID 17097642]
• serum stimulation of fibroblasts in floating matrices does not result in ERK translocation to the nucleus and there was decreased serum activation of upstream members of the ERK signaling pathway, MEK and Raf. [PMID 12663662]
• Affinity Capture-Western [PMID 11409918]
• Affinity Capture-Western [PMID 11409918]
• Increased Raf-1 kinase is associated with glioma formation [PMID 18472967]
• Affinity Capture-Western; Two-hybrid [PMID 19805522]
• Thus, the short hairpin-looped ODN-Raf, targeting the same region of c-raf-1 as miR-125b, is a multifunctional molecule reducing the expression of oncoproteins and stimulating cell death. [PMID 19825990]
• dephosphorylation of S259 is the primary pathogenic mechanism in the activation of RAF1 mutants located in the CR2 domain as well as of downstream ERK [PMID 20052757]
• Raf-1 was dominant in terms of promoting both cell cycle progression and preventing apoptosis when compared to Akt-1 [PMID 20372086]
• the Rb/Raf-1 interaction has a role in cell proliferation and angiogenesis [PMID 18483265]
• PP2A ABalphaC and ABdeltaC holoenzymes function as positive regulators of Raf1-MEK1/2-ERK1/2 signaling by targeting Raf1 [PMID 16239230]
• Raf-1 links mitogenic signaling to Retinoblastoma Protein and that disruption of this interaction could aid in controlling proliferative disorders [PMID 15485920]
• Affinity Capture-Western; Biochemical Activity; Reconstituted Complex; Two-hybrid [PMID 15485920]
• Affinity Capture-Western; Reconstituted Complex [PMID 15485920]
• Ras/Raf-1/MEK/ERK signal pathway is important for chemokine ligand CCL2-induced migration activity and matrix metalloproteinase (MMP)-9 expression. [PMID 22138288]
• DC-SIGN was constitutively associated with a signalosome complex consisting of the scaffold proteins LSP1, KSR1 and CNK and the kinase Raf-1. [PMID 19718030]
• Protein arginine methyltransferase 5 regulates ERK1/2 signal transduction amplitude and cell fate through CRAF. [PMID 21917714]
• Affinity Capture-Western [PMID 11005817]
• different pathogens (ie. Mycobacterium tuberculosis, M. leprae, Candida albicans, measles virus, and HIV-1) interacted with DC-SIGN to activate the Raf-1-acetylation-dependent signaling pathway to modulate signaling by different TLRs [PMID 17462920]
• Reconstituted Complex [PMID 2475255]
• Affinity Capture-Western [PMID 21419342]
• Affinity Capture-Western; Reconstituted Complex; Two-hybrid [PMID 9819434]
• Raf-1 interacts with p130. [PMID 9819434]
• Raf-1 interacts with Rb. [PMID 9819434]
• These data show that Ser-259 dephosphorylation contributes to Raf-1 activation by supporting its membrane accumulation rather than by increasing the specific activity of the kinase [PMID 11756411]
• Sprouty4 binds to Raf1 through its carboxy-terminal cysteine-rich domain, and this binding is necessary for the inhibitory activity of Sprouty4. [PMID 12717443]
• Affinity Capture-Western [PMID 12717443]
• Affinity Capture-Western [PMID 12717443]
• Alpha-adducin and Raf-1 kinase are redistributed and localized to the inclusion membrane in Chlamydia and Chlamydophila infected cells. [PMID 19047752]
• Affinity Capture-Western; Reconstituted Complex; Two-hybrid [PMID 8692945]
• Affinity Capture-Western [PMID 8900182]
• Raf-1 may interfere with the role of Rad24 by competing with Rad24 for binding to Cdc25 in DNA repair, bypassing the checkpoint pathway through Cdc25 activation. [PMID 17614099]
• PAK5 is a potent regulator of Raf-1 activity and may control Raf-1 dependent signaling at mitochondria [PMID 18465753]
• Binding of HIV-1 gp120 to CD4 molecules results in the association of Lck and Raf-1, which is abolished by preincubation of the virus with soluble CD4 [PMID 9658081]
• regulated by an N-terminal autoinhibitory domain whose actions are blocked by interaction with Ras [PMID 15710605]
• Interleukin-6, osteopontin and Raf/MEK/ERK signaling modulate the sensitivity of human myeloma cells to alkylphosphocholines. [PMID 22421411]
• activation is regulated by CNK1 [PMID 15845549]
• Affinity Capture-Western; Reconstituted Complex [PMID 9230211]
• Affinity Capture-Western [PMID 10882715]
• Affinity Capture-Western; Two-hybrid [PMID 10882715]
• These studies identify XIAP as a new substrate of Raf-1. [PMID 16964381]
• Raf-1 interacts with Pin1. This interaction was modelled on a demonstrated interaction between human Raf-1 and Pin1 from monkey and unspecified species. [PMID 15664191]
• Raf-1 interacts with ERK2. This interaction was modelled on a demonstrated interaction between human Raf-1 and ERK2 from an unspecified species. [PMID 15664191]
• Raf-1 interacts with Ras. [PMID 15664191]
• Affinity Capture-Western [PMID 17666399]
• Raf-1 has a role in modulating integrin-stimulated ERK activation when bound to CAMKII [PMID 12954639]
• Sorafenib inhibits NSCLC cell growth by targeting B-RAF in cells with wild-type KRAS and C-RAF in those with mutant KRAS. [PMID 19638574]
• Results indicate that the phosphorylation of Ser(338) and Tyr(341) on Raf-1 exerts an important effect on reconfiguring the two MEK1-binding sites. [PMID 12244094]
• Hras interacts with Raf. This interaction was modelled on a demonstrated interaction between Hras and Raf, both from an unspecified species. [PMID 15705808]
• Nras interacts with Raf. This interaction was modelled on a demonstrated interaction between Nras and Raf, both from an unspecified species. [PMID 15705808]
• Activation of the ras/raf-1 signal transduction pathway leads to prominent phenotypic changes that resemble differentiation of gastrointestinal carcinoid cells in vitro. [PMID 12490852]
• Affinity Capture-Western; Reconstituted Complex [PMID 11044439]
• ndings demonstrate that Pak1 phosphorylates BAD directly at S111, but phosphorylated S112 through Raf-1. [PMID 22096607]
• Bcl-2-associated anthanogene 1 (BAG-1)’s effects were associated with an activation of RAF-1-a known binding partner of BAG-1, enhanced signaling through the MAP kinase pathway and a decrease in BIM expression. [PMID 19881545]
• AhR is a master regulator of c-raf and propose cross-talk between AhR and the mitogen-activated protein kinase signaling pathway. [PMID 18708364]
• targeted expression inhibits juvenile myelomonocytic leukemia cell growth [PMID 12010819]
• Affinity Capture-Western [PMID 14597674]
• essential role of Ras-induced conformational change in mitogen-activated protein kinase kinase activation by c-Raf [PMID 15711535]
• The H-Ras-ERK-induced and HO-1-mediated pathway could protect renal cancer cells from apoptosis. [PMID 21808062]
• In contrast to C-RAF that requires farnesylated H-Ras, cytosolic B-RAF associates effectively and with significantly higher affinity with both farnesylated and nonfarnesylated H-Ras. [PMID 17635919]
• A conserved acidic sequence motif in HIV-1 Nef at positions 174-179 binds to c-Raf1; the interaction of Nef with c-Raf1 leads to a downstream transduction of cell signaling through the c-Raf1-MAP kinase pathway in vivo [PMID 12734410]
• Activation of raf-1 leads to cessation of cell growth and suppression of calcitonin and chromogranin A production [PMID 16029117]
• Raf1 kinase is released when it is hyperphosphorylated and activated during oxidative and other stresses [PMID 15314064]
• Reconstituted Complex [PMID 8876196]
• study identified a group of melanomas with low-activity BRAF mutations (G469E- and D594G) that are reliant upon CRAF-mediated survival activity [PMID 18794803]
• Ovarian cancers demonstrate differential sensitivity to antisense oligonucleotides targeted against Raf-1, and target expression levels. [PMID 15041731]
• RKIP interacts with Raf-1. This interaction was modelled on a demonstrated interaction between RKIP from an unspecified species and Raf-1 from an unspecified species. [PMID 14654844]
• Raf1 and MAPK-activated protein kinase 2 are activated by L-ascorbic acid in acute myeloid leukemia cells. [PMID 15451031]
• Reconstituted Complex; Two-hybrid [PMID 10783161]
• Affinity Capture-Western [PMID 10783161]
• Two-hybrid [PMID 10783161]
• results show overexpression of RAF-1 in mantle cell leukemia compared with tonsilar B-lymphocytes [PMID 17572489]
• Affinity Capture-MS; Affinity Capture-Western [PMID 21139048]
• GRP78 may stabilize Raf-1 to maintain mitochondrial permeability and thus protect cells from endoplasmic reticulum stress-induced apoptosis. [PMID 18064632]
• Affinity Capture-Western; Reconstituted Complex [PMID 18064632]
• The induction of the raf-1/MEK1 pathway blocks IGF-1-mediated intracellular neuroendocrine hormone regulation. This pathway may be a therapeutic target in gastrointestinal carcinoid tumor therapy. [PMID 15657590]
• High RAF1 is associated with hepatocellular carcinoma. [PMID 22110214]
• These results suggest that oncogenic ras-p21 induces phosphorylation of both raf-Ser259 and Ser338 and that raf-Ser 259 phosphorylation may be effected by activated JNK. [PMID 18316782]
• results suggest that activated JNK can, in turn, activate not only jun but also raf that, in turn, activates MEK that can then cross-activate JNK in a positive feedback loop [PMID 16086581]
• Data show that sorafenib inhibited the raf/ MEK/ERK signal pathway, and downregulated cyclin D1 and Rb levels. [PMID 19633425]
• Affinity Capture-Western [PMID 16537561]
• The 1,25(OH)(2)D3-responsive element in cystatin A gene is identical to TRE, T2 (-272 to -278). Suppression of Raf-1/MEK1/ERK1,2 signaling pathway increases cystatin A expression of normal human keratinocytes. [PMID 12682854]
• Rodent and human tumor cells containing constitutively activated Raf/Raf/MEK/ERK pathways were resistant to mda-5-induced killing. [PMID 16575407]
• JNK1, Raf-1 and Livin may be involved in the carcinogenesis of sporadic colorectal tubular adenoma. [PMID 21122381]
• Affinity Capture-Western [PMID 8939988]
• Raf-1 interacts with Rap2. This interaction was modeled on a demonstrated interaction between Raf-1 from unspecified species and human Rap2. [PMID 15752761]
• Mutations in the RAF1 are associated with Noonan syndrome. [PMID 19020799]
• Raf-1 in beta-cells led to a striking loss of Bad phosphorylation at serine 112 and an increase in the protein levels of both Bad and Bax [PMID 18006502]
• study demonstrates a novel role of the Raf/MEK/ERK pathway in regulating AR expression in certain PCa types and provides an insight into PCa responses to its aberrant activation [PMID 21871886]
• The C-Raf expression is up-regulated in a subset of melanomas but not in nevi, suggesting that it might be a valuable diagnostic marker and therapeutic target. [PMID 19737955]
• Vitamin D3-triggered differentiation of human myeloid leukemia cells depends on downregulation of Akt, which dissociates from Raf1 and activates MAPK signaling. [PMID 19058874]
• Reconstituted Complex [PMID 14724584]
• Observational study of gene-disease association. (HuGE Navigator) [PMID 20543023]
• Raf-1 may mediate its anti-apoptotic function by interrupting ASK1-dependent phosphorylation of ALG-2. [PMID 15925322]
• Affinity Capture-Western; Reconstituted Complex [PMID 10969079]
• MEKK1 interacts with Raf-1. [PMID 10969079]
• RAF1 promotes herpesvirus 8 infection. [PMID 15122343]
• EZH2 expression-mediated downregulation of DNA damage repair leads to accumulation of recurrent RAF1 gene amplification in breast tumor initiating cells (BTICs), which activates p-ERK-beta-catenin signaling to promote BTIC expansion. [PMID 21215703]
• Raf-1 interacts with 14-3-3 zeta. This interaction was modelled on a demonstrated interaction between human Raf-1 and murine 14-3-3-zeta. [PMID 7559537]
• Co-purification [PMID 8349631]
• Raf interacts with Ras. This interaction was modeled on a demonstrated interaction between Raf and an unspecified source and human Ras. [PMID 8307946]
• Affinity Capture-Western [PMID 11325826]
• Studies indicate that Raf kinases are excellent molecular targets for anticancer therapy. [PMID 21577205]
• phosphorylation by p21-activated kinase 1 and Src regulates Raf-1 autoinhibition [PMID 12551923]
• RAF may induce cell proliferation through hypermethylation of tumor suppressor gene p16INK4A [PMID 19037990]
• Based on these findings, we speculate that Raf-1 is activated to effectively mediate Ras-dependent signals in Alzheimer’s disease. [PMID 17064357]
• Study reports that 18 of 231 individuals with Noonan syndrome and 2 of 6 individuals with LEOPARD syndrome without PTPN11 mutations have missense mutations in RAF1, which encodes a serine-threonine kinase that activates MEK1 and MEK2. [PMID 17603483]
• Raf interacts with Ras. This interaction was modeled on a demonstrated interaction between human Raf and rat Ras. [PMID 11585923]
• Co-crystal Structure; Reconstituted Complex; Two-hybrid [PMID 10454553]
• Affinity Capture-MS [PMID 15778465]
• Affinity Capture-Western; Co-fractionation; Reconstituted Complex; Two-hybrid [PMID 10585452]
• LEOPARD syndrome, both with proven mutations in the RAF1 gene not previouslyreported [PMID 22389993]
• These results suggest that 0.05 Gy of ionizing radiation stimulates cell proliferation through the transient activation of Raf and Akt in CCD-18 Lu cells. [PMID 18182859]
• Changes in flexibility upon protein-protein complex formation of H-Ras &amp; the Ras-binding domain of C-Raf1 have been investigated using the molecular framework approach FIRST and molecular dynamics simulations of in total approximately 35 ns length. [PMID 15211515]
• Raf-1 may be involved in angiogenesis by controlling the expression of angiogenesis-related factors; study provides a possible strategy for the treatment of tumor angiogenesis by targeting Raf-1 [PMID 15662129]
• Affinity Capture-Western; Two-hybrid [PMID 8702721]
• RAF1 (c-Raf) interacts with an unspecified isoform of PPP2R2C (PP2A-C). [PMID 16041367]
• RAF1 (c-Raf) interacts with an unspecified isoform of PPP2R2B (PP2A-B). [PMID 16041367]
• RAF1 (c-Raf) interacts with PHB. [PMID 16041367]
• RAF1 (c-Raf) interact with an unspecified isoform of PPP2R2A (PP2A-A). [PMID 16041367]
• Affinity Capture-Western; Reconstituted Complex; Two-hybrid [PMID 8929532]
• Reconstituted Complex [PMID 8929532]
• RAS signaling in colorectal carcinomas through alteration of RAS, RAF, NF1, and/or RASSF1a. [PMID 18592002]
• Raf-1 phosphorylation on serine 338 (S338) is a critical step in EGF aktivation of ERK that is lost in nonadherent cells. [PMID 15899852]
• Affinity Capture-Western [PMID 9446616]
• a novel Ras-independent ERK1/2 activation system in which p110gamma/Raf-1/MEK1/2 and PKA/B-Raf/MEK1/2 cooperate to activate ERK1/2. [PMID 15653554]
• Affinity Capture-Western; Reconstituted Complex [PMID 10523633]
• the molecular interactions of arrestin2 and arrestin3 and their individual domains with the components of the two MAPK cascades, ASK1-MKK4-JNK3 and c-Raf-1-MEK1-ERK2 [PMID 19001375]
• Affinity Capture-Western; Reconstituted Complex [PMID 19197339]
• Studies provide models for Ras in association with Raf kinase, RalGDS and PI3Kalpha and PI3Kgamma. [PMID 19801192]

PubMed Articles

Recent articles:

• Leontovich AA et al. “Raf-1 oncogenic signaling is linked to activation of mesenchymal to epithelial transition pathway in metastatic breast cancer cells.” Int J Oncol. 2012 Jun;40(6):1858-64. PMID 22447278
• Yosifov DY et al. “Interleukin-6, osteopontin and Raf/MEK/ERK signaling modulate the sensitivity of human myeloma cells to alkylphosphocholines.” Leuk Res. 2012 Jun;36(6):764-72. PMID 22421411
• Stoeckius M et al. “Essential roles of Raf/extracellular signal-regulated kinase/mitogen-activated protein kinase pathway, YY1, and Ca2+ influx in growth arrest of human vascular smooth muscle cells by bilirubin.” J Biol Chem. 2012 May 4;287(19):15418-26. PMID 22262839
• Kuburović V et al. “Two cases of LEOPARD syndrome–RAF1 mutations firstly described in children.” Turk J Pediatr. 2011 Nov-Dec;53(6):687-91. PMID 22389993
• Andersen SD et al. “14-3-3 checkpoint regulatory proteins interact specifically with DNA repair protein human exonuclease 1 (hEXO1) via a semi-conserved motif.” DNA Repair (Amst). 2012 Mar 1;11(3):267-77. PMID 22222486
• Tang CH et al. “CCL2 increases MMP-9 expression and cell motility in human chondrosarcoma cells via the Ras/Raf/MEK/ERK/NF-κB signaling pathway.” Biochem Pharmacol. 2012 Feb 1;83(3):335-44. PMID 22138288
• Mielgo A et al. “A MEK-independent role for CRAF in mitosis and tumor progression.” Nat Med. 2011 Nov 13;17(12):1641-5. PMID 22081024
• Ye DZ et al. “p21-Activated kinase 1 (Pak1) phosphorylates BAD directly at serine 111 in vitro and indirectly through Raf-1 at serine 112.” PLoS One. 2011;6(11):e27637. PMID 22096607
• Ceteci F et al. “Conditional expression of oncogenic C-RAF in mouse pulmonary epithelial cells reveals differential tumorigenesis and induction of autophagy leading to tumor regression.” Neoplasia. 2011 Nov;13(11):1005-18. PMID 22131876
• Hoffmann K et al. “Correlation of gene expression of ATP-binding cassette protein and tyrosine kinase signaling pathway in patients with hepatocellular carcinoma.” Anticancer Res. 2011 Nov;31(11):3883-90. PMID 22110214

Top Pubmed articles linked to gene RAF1 matching any search term:

• Kalderon B et al. “Suppression of adipose lipolysis by long-chain fatty acid analogs.” J Lipid Res. 2012 May;53(5):868-78. PMID 22338010
• Ku HC et al. “Green tea (-)-epigallocatechin gallate inhibits IGF-I and IGF-II stimulation of 3T3-L1 preadipocyte mitogenesis via the 67-kDa laminin receptor, but not AMP-activated protein kinase pathway.” Mol Nutr Food Res. 2012 Apr;56(4):580-92. PMID 22495985
• Bonilla AQ et al. “Developmental changes in thermoprotective actions of insulin-like growth factor-1 on the preimplantation bovine embryo.” Mol Cell Endocrinol. 2011 Jan 30;332(1-2):170-9. PMID 20965229
• Okuyama T et al. “The ERK-MAPK pathway regulates longevity through SKN-1 and insulin-like signaling in Caenorhabditis elegans.” J Biol Chem. 2010 Sep 24;285(39):30274-81. PMID 20624915
• Sangle GV et al. “Involvement of RAGE, NADPH oxidase, and Ras/Raf-1 pathway in glycated LDL-induced expression of heat shock factor-1 and plasminogen activator inhibitor-1 in vascular endothelial cells.” Endocrinology. 2010 Sep;151(9):4455-66. PMID 20630999
• Kawaguchi M et al. “Induction of insulin-like growth factor-I by interleukin-17F in bronchial epithelial cells.” Clin Exp Allergy. 2010 Jul;40(7):1036-43. PMID 20642578
• Xie P et al. “Pathobiology of renal-specific oxidoreductase/myo-inositol oxygenase in diabetic nephropathy: its implications in tubulointerstitial fibrosis.” Am J Physiol Renal Physiol. 2010 Jun;298(6):F1393-404. PMID 20335317
• Park KH et al. “Mechanism of insoluble phosphate solubilization by Pseudomonas fluorescens RAF15 isolated from ginseng rhizosphere and its plant growth-promoting activities.” Lett Appl Microbiol. 2009 Aug;49(2):222-8. PMID 19486289
• Ku HC et al. “Green tea (-)-epigallocatechin gallate inhibits insulin stimulation of 3T3-L1 preadipocyte mitogenesis via the 67-kDa laminin receptor pathway.” Am J Physiol Cell Physiol. 2009 Jul;297(1):C121-32. PMID 19176763
• Padidela R et al. “Abnormal growth in noonan syndrome: genetic and endocrine features and optimal treatment.” Horm Res. 2008;70(3):129-36. PMID 18663312
• MacLaren R et al. “Influence of obesity and insulin sensitivity on insulin signaling genes in human omental and subcutaneous adipose tissue.” J Lipid Res. 2008 Feb;49(2):308-23. PMID 17986714
• Alejandro EU et al. “Inhibition of Raf-1 alters multiple downstream pathways to induce pancreatic beta-cell apoptosis.” J Biol Chem. 2008 Jan 25;283(4):2407-17. PMID 18006502
• Xiang X et al. “Phosphorylation of 338SSYY341 regulates specific interaction between Raf-1 and MEK1.” J Biol Chem. 2002 Nov 22;277(47):44996-5003. PMID 12244094
• Murphy GA et al. “Involvement of phosphatidylinositol 3-kinase, but not RalGDS, in TC21/R-Ras2-mediated transformation.” J Biol Chem. 2002 Mar 22;277(12):9966-75. PMID 11788587
• Zang M et al. “Interaction between active Pak1 and Raf-1 is necessary for phosphorylation and activation of Raf-1.” J Biol Chem. 2002 Feb 8;277(6):4395-405. PMID 11733498
• Bourbon NA et al. “Inhibitory actions of ceramide upon PKC-epsilon/ERK interactions.” Am J Physiol Cell Physiol. 2001 Jun;280(6):C1403-11. PMID 11350735
• Nantel A et al. “Interaction of the Grb10 adapter protein with the Raf1 and MEK1 kinases.” J Biol Chem. 1998 Apr 24;273(17):10475-84. PMID 9553107
• Luo ZJ et al. “Identification of the 14.3.3 zeta domains important for self-association and Raf binding.” J Biol Chem. 1995 Oct 6;270(40):23681-7. PMID 7559537
• Brtva TR et al. “Two distinct Raf domains mediate interaction with Ras.” J Biol Chem. 1995 Apr 28;270(17):9809-12. PMID 7730360
• Zhang XF et al. “Normal and oncogenic p21ras proteins bind to the amino-terminal regulatory domain of c-Raf-1.” Nature. 1993 Jul 22;364(6435):308-13. PMID 8332187