LIFE01200604005 Shri Somnath Ghosh - Homi Bhabha National ...

CHAPTER 1
INTRODUCTION
Cytoprotective Response Cascade
The term cytoprotective describes the summation of responses which favor cell survival
and may span from enhanced repair functions to stimulation of proliferation. These
responses may be initiated at the level of the plasma membrane through activation of
ERBB receptor tyrosine kinases and other related molecules [172]. Several lines of
investigation support that the loss of EGFR/ERBB2 function radiosensitizes tumor cells
[172-174].
The radiation-induced activation of EGFR has been linked mechanistically to
enhanced signaling through critical components of the MAPK and MAPK8 pathways
[172, 175]. These links are based on inhibition of the function of EGFR by over
expression of dominant-negative mutants [173, 176] or the use of specific
pharmacological inhibitors, such as the tyrphostin AG1478 [172]. The disruption of
function of ERBB2 may exert similar effects. The radiation-induced activation of EGFR
at doses between 1 and 5 Gy [169] results in the activation of several immediate
downstream effectors. Tyr phosphorylation of EGFR at positions Tyr1068, Tyr1148 and
Tyr1173 (30) permits interaction with adapter proteins GRB2 and SHC, which in turn act
through factors to stimulate GTP for GDP exchange in RAS. Radiation-induced
activation of EGFR also results in the stimulation of PLCγ with production of
diacylglyceride and inositol trisphosphate (IP3)[172, 177]. Diacylglyceride activates
protein kinase C (PRKC) and IP3 induces release of Ca 2+ from intracellular stores [172,
178, 179]. RAS-GTP recruits RAF1 to the plasma membrane; this activation is dependent
on the release of Ca 2+ from intracellular stores [177, 178, 180]. RAF1 primarily signals
along the MAPK cascade involving MAP2K1/2 and p90S6 kinase [180]. MAPK and
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