Download Gene Section RAF1 (v-raf-1 murine leukemia viral oncogene homolog 1)

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Gene Section
Review
RAF1 (v-raf-1 murine leukemia viral oncogene
homolog 1)
Max Cayo, David Yu Greenblatt, Muthusamy Kunnimalaiyaan, Herbert Chen
Endocrine Cancer Disease Group, University of Wisconsin Paul P. Carbone Comprehensive Cancer Center,
H4/750 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792, USA
Published in Atlas Database: March 2007
Online updated version: http://AtlasGeneticsOncology.org/Genes/RAF1ID42032ch3p25.html
DOI: 10.4267/2042/38452
This work is licensed under a Creative Commons Attribution-Non-commercial-No Derivative Works 2.0 France Licence.
© 2007 Atlas of Genetics and Cytogenetics in Oncology and Haematology
encoding for the serine/threonine kinase domain) in the
C terminus. The RAF proteins exhibit complex
regulation involving numerous phosphorylation sites
throughout the proteins. Despite constitutional
similarity, the Raf isoforms have been shown to carry
out non-redundant functions, implying that they are
distinct.
RAF-1 (C-RAF-1): 72-74 kDa.
Note: A-RAF: about 68 kDa.
Note: B-RAF (which undergoes alternate splicing):
ranges from 75 to 100 kDa.
Identity
Hugo: RAF1
Other names: CRAF; Raf-1; c-Raf
Location: 3p25
DNA/RNA
Note: History and Nomenclature:
c-Raf-1 was the first successfully cloned functional
human homolog of the v-Raf gene, and thus the gene
product of c-Raf-1 has historically been referred to in
the literature simply as Raf-1. Subsequently, B-Raf and
A-Raf-1 paralogues (BRAF, located in Xq13 and
ARAF, located in Xp11) were discovered. A suitable
nomenclature is as follows: A-RAF, B-RAF, and CRAF for the functional human proteins and A-RAF, BRAF, and C-RAF for the corresponding genes; a-raf, braf, and c-raf for the murine proteins and A-Raf, B-Raf,
and C-Raf for the corresponding genes. Raf-1 (or RAF1) is generally taken to mean C-RAF-1 but could apply
to A-RAF-1 equally. Here, RAF-1 will be taken to
mean C-RAF-1 (RAF-1 = C-RAF-1, etc.).
Expression
C-RAF (RAF-1) and A-RAF mRNA is expressed
ubiquitously. A-RAF mRNA is highly expressed in
urogenital organs. B-RAF is expressed in a wide range
of tissues, but most substantially in neuronal tissues.
Localisation
Cytosolic.
Function
RAF proteins are part of the conserved MAPK
(mitogen-activated protein kinase)/ERK (extracellular
signal-regulated kinase) signaling cascade between the
cell surface and the nucleus. RAF is regulated by the
upstream RAS family of small G proteins. RAS is
predominantly located on the inner leaflet of the plasma
membrane and is functionally activated by GTPbinding. Binding of various extracellular ligands such
as growth factors and hormones activates RAS and
subsequently RAF proteins. RAS binds directly to the
N-terminal regulatory domain or RAF (the RAS
binding domain (RBD)). RAS interacts secondarily
with the cysteine-rich domain (CRD) on CR1 of RAF.
RAS-RAF binding can be affected by 14-3-3 proteins
and other scaffold/adaptor proteins kinase suppressor of
Description
C-RAF (RAF-1, C-RAF-1) encompasses 80,570 bp of
DNA; 17 Exons.
Transcription
RAF-1 transcribed
nucleotides.
mRNA
contains
3212-3216
Protein
Description
The RAF proteins share three conserved domains: two
(CR1 and CR2) in the N terminus and a third (CR3-
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Cayo M et al.
RAS (KSR), the multidomain protein connectorenhancer of KSR (CNK), and the leucine-rich-repeat
protein suppressor of RAS mutations-8 (SUR8), which
cause formation of various homo- and heterodimers
and subsequently affect signal transduction. RAF
activation leads to activation of the protein kinases
MEK1 and MEK2 and subsequently the MAPK
proteins ERK1 and ERK2. The downstream effects of
MEK1/2-ERK1/2 activation are varied, complex, and
depend on the cellular context. Resultant effects
include activation of transcription factors involved in
tumorigenesis, cell growth, survival, differentiation,
metabolism, and cytoskeletal rearrangements. RAF-1
(C-RAF-1), A-RAF, and B-RAF are all capable of
activating the MEK1/2-ERK1/2 signaling pathway.
RAF-1 is capable of activating the NF-kB transcription
factor through an unknown mechanism that does not
seem to involve direct phosphorylation of NF-kB and is
independent of MEK1/2-ERK1/2 signaling.
RAF-1 is known to directly affect cell survival through
phosphorylation
of
BAG1
(BCL2-associated
athanogene-1), an anti-apoptotic protein that binds to
BCL2, a second anti-apoptotic factor, also the
prototype for a family of mammalian genes involved in
mitochondrial outer membrane permeability (MOMP),
thus restoring its function. BCL2 also targets RAF-1 to
the mitochondrial membrane, where it is able to more
readily phosphorylate substrates. The RAF1/BAG1/BCL2 interaction allows RAF-1 to
phosphorylate the pro-apoptotic protein BAD at the
mitochondrial membrane, promoting cell survival.
Other known substrates of RAF-1 include the
phosphatase CDC25C, the apoptosis signal-regulating
kinase-1 (ASK1), and the tumor-suppressor protein
retinoblastoma (Rb).
RAF-1 is tightly regulated by the AKT/PKB pathway
through phosphorylation at S259.
of all cases. MTC cells secrete hormones and tumor
markers such as calcitonin, chromogranin A (CgA),
and carcinoembryonic antigen (CEA).
Symptoms are related to either direct invasion or
metastasis (neck mass, dyspnea, dysphagia, voice
changes, pain) or tumor secretion of bioactive amines
and peptides (diarrhea, flushing).
Prognosis
Currently, surgery is the only potentially curative
therapy for patients with MTC. The recommended
operation is total thyroidectomy with lymph node
dissection. However, 50% of patients treated with
surgery suffer persistent or recurrent disease.
Oncogenesis
20% of patients with medullary thyroid cancer have an
autosomal dominant inherited form of the disease,
which is the result of well-characterized point
mutations in the RET proto-oncogene. RAF-1 is
conserved but not expressed at baseline in MTC. Preclinical studies have shown that activation of RAF-1 in
MTC (TT) cells by means of RAF-1 gene transfection
or RAF-1 activating small molecules (ZM336372)
results in tumor cell growth inhibition in vitro and in
vivo.
Carcinoid Tumors
Disease
Carcinoids are tumors that arise from the diffuse
neuroendocrine cell system of the gut, lungs, and other
organs. The incidence is 1-5 per 100,000 individuals.
Carcinoids frequently metastasize to the liver and are
the second most common source of isolated liver
metastases. Carcinoids secrete various bioactive
hormones such as 5-HT (5-hydroxy tryptophan, also
known as serotonin) and chromogranin A.
Prognosis
Patients with hepatic metastases suffer debilitating
symptoms such as abdominal pain, flushing,
bronchoconstriction, and diarrhea. Palliative treatment
for these hormone-induced symptoms includes
somatostatin analogs (such as octeotride). Conventional
anticancer treatments such as chemotherapy and
external beam radiation are largely ineffective for
carcinoid tumors.
Oncogenesis
RAF-1 activation is detrimental to tumorigenesis in
carcinoid cells. Marked reduction in neuroendocrine
phenotypic markers such as human achaete-scute
complex like-1 (ASCL-1) and bioactive hormones 5HT, chromogranin A, and synaptophysin has been
noted upon RAF-1 activation using an estrogeninducible RAF-1 construct in human GI (BON) and
pulmonary carcinoid cell lines (NCI-H727).
Treatment of GI carcinoid cells with RAF-1 activator
ZM336372 led to a decrease in bioactive hormone
levels, a suppression of cellular proliferation, an
Mutations
Somatic
It has been widely established that RAF-1 over activity,
typically via ras-activating mutations, is central to
tumorigenesis and cell proliferation in numerous
cancers (about 30% of all human cancers). However, it
has come to the fore that oncogenesis may be due to
ras/RAF-1 dysregulation (either increased or decreased
expression) rather than increases in ras/RAF-1 activity
exclusively.
Implicated in
Medullary Thyroid Cancer (MTC)
Disease
A neuroendocrine tumor derived from parafollicular C
cells of the thyroid gland, MTC is the third most
common form of thyroid cancer, accounting for 3-5%
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RAF1 (v-raf-1 murine leukemia viral oncogene homolog 1)
Cayo M et al.
increase in cell cycle inhibitors p21 and p18, as well as
a decrease in the neuroendocrine phenotypic marker
ASCL-1. ZM336372 treatments also led to progressive
phosphorylation (activation) of MEK1/2, ERK1/2, and
RAF-1.
leads to decreased cell proliferation. RAF-1 activation
in pheochromocytoma cells using ZM336372 led to
cellular differentiation, growth arrest, and a decrease in
the neuroendocrine marker chromogranin A.
Non-Neuroendocrine Cancers with rasactivating Mutations
Small Cell Lung Cancer (SCLC)
Disease
SCLC tends to present with metastatic and regional
spread. Carcinoids rarely metastasize, arise from major
bronchi, and express neuron-specific enolase,
chromogranin, and synaptophysin. Neuroendocrine
carcinoids or atypical carcinoids have a more
aggressive course.
Oncogenesis
Human small-cell lung cancer (SCLC) cell lines rarely
harbor ras-activating mutations. In one cell line of
SCLC, DMS53, it was shown that by RAF-1 induction
using an estrogen-inducible RAF-1 construct SCLC
cells underwent differentiation and G1-specific growth
arrest in conjunction with MEK/ERK1/2 pathway
activation.
Oncogenesis
About 30% of all human cancers express ras-activating
mutations.
More
than
85%
of
pancreatic
adenocarcinomas and 50% of colonic adenocarcinomas
harbor K-ras mutations. K-ras is an upstream effector
of RAF-1 in the RAF-1/MEK/ERK1/2 signaling
pathway. Ras mutations have also been linked to
tumorigenesis of cholangiocarcinoma, adenocarcinoma
of the lung, squamous cell cancer, gastric
adenocarcinoma, small bowel adenocarcinoma, and
malignant melanoma.
Colorectal Cancer
Oncogenesis
RAF-1 is over-activated due to oncogenic ras mutations
in about 50% of colon cancers. These mutations are
associated with poor prognosis, and are necessary for
maintenance of the malignant phenotype.
RAF-1 inhibition in response to interaction with RAF
kinase inhibitor protein (RKIP) (up-regulated in
conjunction with the nuclear factor kappa B signaling
pathway) has been linked with overall and disease-free
survival in patients with colorectal cancers. RKIP has
been identified as potentially useful for identifying
early-stage CRC patients at risk for relapse.
Non-Small Cell Lung Cancer (NSCLC)
Disease
Adenocarcinoma is the most common type of NSCLC
accounting for about 40% of cases. Lesions are
generally located peripherally and develop systemic
metastases despite small primary tumors. 25% of
NSCLC are squamous cell carcinomas which often
remain localized.
Oncogenesis
RAF-1 is over-expressed due to oncogenic ras
mutations in about 35% of NSCLC.
The majority of NSCLC exhibits EGFR overexpression leading to upregulation of RAF-1 activity.
NSCLC has been shown to be mediated by a TGF-a
/EGFR-mediated autocrine loop activated by signaling
involving RAF-1 and PI3K-Akt.
Pancreatic Carcinoma
Oncogenesis
RAF-1 is overactivated due to oncogenic ras mutations
in about 90% of pancreatic carcinomas (Panc-1 and
Mia-PaCa2). It has been shown that malignancy of
these cells is reduced using k-ras RNAi.
Pharmacological inhibition of the RAF/MEK/ERK
pathway in pancreatic cancer cell lines (via MEK
inhibition) results in reduction in cellular proliferation
and an increase in cell cycle arrest.
Pheochromocytoma
Disease
Pheochromocytomas are neuroectodermal in origin and
arise from the chromaffin cells of the adrenal medulla.
10% of tumors are bilateral. Typical symptoms such as
hypertension, headaches, diaphoresis, palpitations,
diarrhea, and skin rashes, are related to tumor
production of catecholamines, especially in patients
with metastases. Pheochromocytoma is potentially
fatal, but relatively uncommon (2-8 cases per million
people annually). Curative therapy is surgery, usually
accomplished by laparoscopic adrenalectomy.
Oncogenesis
Activation of MEK1/2-ERK1/2 is necessary for
differentiation of pheochromocytoma (PC12) cells and
Atlas Genet Cytogenet Oncol Haematol. 2007;11(3)
Hepatocellular Carcinoma (HCC)
Oncogenesis
RAF-1 is over-activated in about 50% of biopsies while
the RAF-1 protein is over-expressed in nearly 100% of
all HCC's. Angiogenesis and other functions essential
to tumorigenesis in HCC have been reported to depend
on the RAF/MEK/ERK signaling pathway. RAF-1
inhibitor Sorafenib has been reported (in-vitro and invivo) to inhibit RAF-1 activity, leading to decreased
MEK/ERK activity, reduced cellular proliferation, and
apoptosis in several HCC cell lines including HepG2
and PLC/PRF/5.
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Cayo M et al.
Prostate Cancer
Renal Cell Carcinoma
Oncogenesis
RAF kinase inhibitor protein (RKIP) coding mRNAs
have been observed to activate interferon-inducible
2',5'-oligoadenylate synthetases (OAS). OAS activity is
characteristically increased (via these mRNAs) in
prostate cancer cell lines PC3, LNCaP and DU145.
RKIP expression is detectable in primary prostate
cancer sections but not in metastases. This suggests
RKIP's characterization as an anti-metastasis gene
using the RAF/MEK/ERK signaling pathway is
appropriate.
RAF-1 inhibition using systemically delivered novel
cationic cardiolipin liposomes (NeoPhectin-AT)
containing a small interfering RNA (siRNA) against
RAF-1 causes tumor growth inhibition in a xenograft
model of human prostate cancer.
RAF/MEK/ERK signaling pathway activation via a
biologically active peptide called a prosaptide (TX14A)
stimulates cell proliferation/survival, migration, and
invasion in human prostate cancer cells.
NSC 95397 and NSC 672121, cdc25 inhibitors, were
shown to activate the RAF/MEK/ERK pathway in
prostate cancer cells.
RAF-1 activation in LNCaP prostate cancer cells using
an estrogen-inducible construct led to growth
inhibition.
Oncogenesis
RAF-1 is overactivated in conjunction with loss of
function of the VHL (von Hippel-Lindau) tumorsuppressor gene.
Breast Cancer
Oncogenesis
RAF-1 inactivation using RNAi in gastric cancer cell
line SGC7901 led to dramatic reductions in
angiogenesis, increased apoptosis, and decreased
cellular proliferation.
Glioma
Oncogenesis
RAF-1 inhibitor AAL881 inhibited growth of glioma
cell xenografts.
Cervical Cancer
Oncogenesis
Low RAF-1 kinase activity is significantly associated
with paclitaxel sensitivity in cervical cancers.
Ovarian Cancer
Oncogenesis
RAF-1 dysregulation is associated with poor prognosis
and possibly carcinogenesis. RAF-1 inhibition using
RNAi reduces cellular proliferatin and inhibits ovarian
tumor cell growth in vitro and in vivo. Similar results
were observed using antisense oligonucleotide (ASO)
therapy (ISIS 5132 and ISIS 13650).
RAF-1 inhibition by the Akt pathway sensitizes human
ovarian cancer cells to the drug paclitaxel.
Gastric Cancer
Oncogenesis
Growth hormone releasing hormone (GHRH) has been
shown to regulate breast cancer cell proliferation and
differentiation. In MDA-231 breast cancer cells,
exogenous
GHRH
stimulated
dose-dependent
proliferation. RAF-1 inhibition using the agent
PD98059 caused prevention of MAPK phosphorylation
by GHRH as well as reduced cellular proliferation.
Proliferative effects of steroid hormone estradiol on
MCF-7 breast cancer cells have been linked with
increased expression of RAF-1, possibly due to direct
activation of RAF-1 by estradiol.
RAF kinase inhibitor protein (RKIP) is associated with
metastasis suppression. RKIP expression is lost in
lymph node metastases. This suggests RKIP is a
metastasis inhibitor gene and that RAF-1 expression
enables metastasis.
The PTK inhibitor AG 879 inhibits proliferation of
human breast cancer cells through inhibition of MAP
kinase activation through inhibition of expression of
the RAF-1 gene.
RAF-1 down-regulation is associated with paclitaxel
drug resistance in human breast cancer cell line MCF7/Adr.
Atlas Genet Cytogenet Oncol Haematol. 2007;11(3)
Bladder Cancer
Oncogenesis
RAF-1 gene amplification was detected in 4% of
bladder cancer samples. Deletions at the RAF-1 locus
were detected in 2.2% of these samples. Both
amplifications and deletions were heavily correlated
with high tumor grade (P < 0.00001), advanced stage
(P < 0.0001), and poor survival (P < 0.05).
Lymphoma
Oncogenesis
RAF-1 is typically over-expressed
lymphomas from TCR transgenic mice.
in
thymic
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