LIFE01200604005 Shri Somnath Ghosh - Homi Bhabha National ...

CHAPTER 1
INTRODUCTION
p90S6 kinase regulate diverse targets in cells including transcription factors [181, 182].
RAF1 has also been shown to phosphorylate the antiapoptosis protein BCL2, a
modification that may counteract the anti-apoptosis function of BCL2 [183]. The
importance of RAS lies in its potential cross-communication into the MAPK8 pathway
[173], and the critical role of MAPK as downstream effector of EGFR is demonstrated by
the finding that inhibition of MAPK by PD98059 [173, 184, 185] disrupts the
cytoprotective response against radiation. Also in line with these conclusions are the
findings that both the inhibition of RAS function through inhibition of prenylation [186]
and the down-regulation of RAF1 with antisense-RAF oligonucleotides [187] result in
radiosensitization of human tumor cells.
Increased signaling through the MAPK pathway is cytoprotective after exposure
to radiation, although the precise mechanism(s) by which this occurs is unclear [172, 175,
184, 185]. There is new evidence that the regulatory functions of MAPK on cell
proliferation compared to differentiation vary with cell type and depend on the magnitude
and duration of MAPK activation [188-191]. A short activation of MAPK correlated with
increased proliferation, potentially through coordinated expression induction of cyclin D1
and the cyclin-dependent kinase (CDK) inhibitor CDKN1A (formerly known as p21)
[188, 190, 191]. In contrast, prolonged stimulation of MAPK activity was linked to
decreased DNA synthesis, potentially through super-induction of CDKN1A [188, 189].
This establishes MAPK as an important target for both radiation- and growth factorinduced
activation of EGFR and transient increases in CDKN1A protein levels [184,
192]. High levels of CDKN1A expression would potentially lead to growth arrest at the
G1/S- and G2/ M-phase boundaries, as has been reported for cells exposed to radiation
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