LIFE01200604005 Shri Somnath Ghosh - Homi Bhabha National ...

CHAPTER 1
INTRODUCTION
CD4 (formerly known as p55) and TNFRSF1B (formerly known as p75); only CD4
contains a domain which can directly signal the caspase cascade that leads to apoptosis
[198]. Both receptors can activate the lipid-cleaving enzyme acid sphingomyelinase
(ASMase) with the production of ceramide. Ceramide, through the family of GTPbinding
molecules RHO/RAC and RAS, leads to the activation of downstream signaling
molecules MEKK1/2, which are analogous to RAF1 in the MAPK pathway. Active
MEKK1 in turn can phosphorylate and activate MAP2K4/7 and MAP2K3/6. These
molecules share considerable sequence similarity to MAP2K in the MAPK pathway.
MAP2K4/7 [199] signals to MAPK8, which phosphorylates the transcription factor JUN,
and has been shown to facilitate apoptosis in certain cell types. For example, in several
studies using cells of hematopoietic lineage, enhanced MAPK8 signaling has been
closely associated with apoptosis in response to cytotoxic stimuli [200-202]. In other
nonhematopoietic cells, such as carcinoma cells, increased MAPK8 signaling can result
in increased proliferation and protection from radiation and other cytotoxic stresses [203,
204]. Thus the precise role of MAPK8 activation in response to exposure of cells to
radiation may vary substantially with the cell type analyzed. Alternatively, MAP2K3/6
may signal along a rescue pathway involving MAPK1 (formerly known as p38)
reactivating kinase, which facilitates phosphorylation of heat-shock proteins and cell
survival.
Although much research has been done on low LET induced signaling, there have been
few sporadic and diverse studies with high LET radiation.
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