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Repression of thrombospondin expression was found in

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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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