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Unformatted text preview: pondin expression was found in cells expressing either one of the three
RAS isoforms H-, K-, or NRAS. It seems that c-Jun activation by RAS mediates, or at
least contributes to, thrombospondin gene repression in RAS- transformed cells (96). RAS in differentiation, growth arrest and senescence
Although RAS was originally characterized as a protein with mitogenic and
transforming potential, it has been later shown to have remarkably diverse effects on
cell growth. Besides proliferation and transformation, RAS has been implicated in
cellular events including differentiation, growth arrest, and senescence.
Microinjection of HRAS oncoprotein into mouse pheochromocytoma PC12 cells leads
to reversible neuronal differentiation and growth arrest (97). Expression of oncogenic
HRAS results in growth arrest of rat Schwann cells, whereas these cells are
transformed when RAS co-operates with SV40 large T antigen, adenoviral E1A, or
Myc, and growth arrest is absent. Similar results have been obtained in these cells
with RAF-1 (CRAF), which causes growth arrest via p53-dependent induction of p21
without affecting p27 levels (98). In murine fibroblasts moderate RAF expression is
accompanied by cell cycle progression whereas a robust RAF signal leads to p53independent accumulation of p21 and p21-dependent cell cycle arrest, a phenomenon
not seen in p21-/- cells (98).
Although RAS-induced growth arrest seems to partly rely on p21, also other
23 regulators are required. In primary human and rodent fibroblasts oncogenic HRAS
induces accumulation of the negative growth regulators p53, p21 and p16INK4A and
cellular senescence with irreversible growth arrest. Activation of the MAPK pathway
may lead to opposing growth effects; cell senescence as well as proliferation or
transformation, but the factors determining the response have so far not been
identified. Determinants of the final outcome are suggested to include downstream
cell cycle regulators but also the strength and duration of the RAS-RAF-MAPK
signaling, as seen in the case of RAF (99, 100). Thus it seems that the a...
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