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Dr.
Martin Holcik's Group - Research Interests
I am interested in the investigation of the regulation of
protein synthesis, with specific emphasis on cap-independent
translation, in apoptosis and cancer. Regulation of gene expression
occurs at multiple levels, including translation. Control
at the level of protein synthesis (and/or translation-coupled
mRNA stability) allows cells to respond rapidly to changes
in physiological conditions. Indeed, the repression or activation
of translation occurs almost instantaneously, unlike regulation
at other levels (such as transcription, mRNA processing, or
protein modification and turnover) that entail a considerable
time lag.
We have identified of a novel mechanism of translational
regulation of two key inhibitor of apoptosis (IAP), XIAP and
HIAP2, expression via internal initiation. Our studies demonstrate
that the presence of the IRES (Internal Ribosome Entry Site)
element in the XIAP or HIAP2 mRNAs allow these proteins to
be selectively translated following the repression of cap-dependent
translation of the majority of cellular transcripts. The IRES
regulation of IAP translation points to an important mechanism
in the control and regulation of apoptosis. This is the first
example of anti-apoptotic genes being controlled at the translational
level and this may provide much needed survival activity to
the cell under stressful situations. This mechanism may also
be exploited by cancer cells to escape stressful situations,
such as hypoxia or therapy-induced damage, which would otherwise
induce apoptosis.
Specific research goals of my laboratory are:
- identification of the trans-acting cellular factors that
bind to the XIAP and HIAP2 IRES and modulate their activity,
- analysis of the RNA-protein interactions within the IAP
IRES element;
- analysis of various apoptotic stimuli and stress situations
such as hypoxia, chemotherapeutic drugs and g-irradiation
on the expression of XIAP, HIAP2, and other IRES-containing
mRNAs;
- identification of physiological and pharmacological stimuli
which modulate IRES-mediated translation in general.
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