10.20381/ruor-4562
Jordan, Lindsay
Signalling Towards IRES
Université d'Ottawa / University of Ottawa
2011
XIAP
Bcl-xL
PDCD4
Apaf-1
IRES
S6K2
translation
apoptosis
Université d'Ottawa / University of Ottawa
Université d'Ottawa / University of Ottawa
2011-05-04
2011-05-04
2011
2011
en
Thesis
http://hdl.handle.net/10393/19946
XIAP and Bcl-xL are critical anti-apoptotic molecules that directly inhibit caspases and block mitochondrial membrane permeabilization, respectively. In addition to preventing apoptosis, both XIAP and Bcl-xL can be generated by cap-independent translation via the utilization of an IRES in the 5'-UTR of their mRNAs. In recent years it has been shown that activation of S6K2 induces the translational upregulation of these two apoptotic regulators. Here I have determined that activation of S6K2 enhances IRES-mediated translation of XIAP and Bcl-xL by inducing the degradation of PDCD4, which I have identified as a novel regulator of XIAP and Bcl-xL IRES elements. Furthermore, I have shown that PDCD4 is a positive modulator of the Apaf-1 IRES element. The concurrent regulation of XIAP, Bcl-xL and Apaf-1 by PDCD4 suggests a model in which the level of PDCD4 expression alters the apoptotic threshold by specifically impacting IRES-mediated translation of the XIAP, Bcl-xL and Apaf-1 mRNAs.