Publication: Epigenetic inactivation of the
Ras-association domain family 1 (RASSF1A)
gene and its function in human carcinogenesis
Authors
Dammann, R. ; Schagdarsurengin, U. ; Strunnikova, M. ; Rastetter, M. ; Seidel, C. ; Liu, L. ; Tommasi, S. ; Pfeifer, G.P.
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Publisher
Murcia : F. Hernández
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DOI
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info:eu-repo/semantics/article
Description
Abstract
The Ras GTPases are a superfamily of
molecular switches that regulate cellular proliferation
and apoptosis in response to extra-cellular signals. The
regulation of these pathways depends on the interaction
of the GTPases with specific effectors. Recently, we
have cloned and characterized a novel gene encoding a
putative Ras effector: the Ras-association domain family
1 (RASSF1) gene. The RASSF1gene is located in the
chromosomal segment of 3p21.3. The high allelic loss in
a variety of cancers suggested a crucial role of this
region in tumorigenesis. At least two forms of RASSF1
are present in normal human cells. The RASSF1A
isoform is highly epigenetically inactivated in lung,
breast, ovarian, kidney, prostate, thyroid and several
other carcinomas. Re-expression of RASSF1A reduced
the growth of human cancer cells supporting a role for
RASSF1 as a tumor suppressor gene. RASSF1A
inactivation and K-ras activation are mutually exclusive
events in the development of certain carcinomas. This
observation could further pinpoint the function of
RASSF1A as a negative effector of Ras in a pro-apoptotic
signaling pathway. In malignant mesothelioma and
gastric cancer RASSF1A methylation is associated with
virus infection of SV40 and EBV, respectively, and
suggests a causal relationship between viral infection
and progressive RASSF1A methylation in
carcinogenesis. Furthermore, a significant correlation
between RASSF1A methylation and impaired lung
cancer patient survival was reported, and RASSF1A
silencing was correlated with several parameters of poor
prognosis and advanced tumor stage (e.g. poor
differentiation, aggressiveness, and invasion). Thus,
RASSF1A methylation could serve as a useful marker for
the prognosis of cancer patients and could become important in early detection of cancer.
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