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) which entail a considerable time lag.

Recently, we have identified of a novel mechanism of translational regulation of the X-linked inhibitor of apoptosis, XIAP, expression via internal initiation. Our studies demonstrate that the presence of the IRES (Internal Ribosome Entry Site) element in the XIAP mRNA allows the XIAP protein to be selectively translated following the repression of cap-dependent translation of the majority of cellular transcripts. The IRES regulation of XIAP translation points to an important mechanism in the control and regulation of apoptosis. This is the first example of an anti-apoptotic gene 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:

(i)                  identification of the trans-acting cellular factors that bind to the XIAP IRES and modulate its activity,

(ii)                analysis of the RNA-protein interactions within the IRES element;

(iii)               analysis of various apoptotic stimuli and stress situations such as hypoxia, chemotherapeutic drugs and g-irradiation on the expression of XIAP, and other IRES-containing mRNAs;

(iv)              identification of physiological and pharmacological stimuli which modulate IRES-mediated translation.

Recent Publications: 

Nevins, T., Harder, Z.M., Korneluk, R.G. and Holcik, M. (2003) Distinct regulation of IRES-mediated translation following cellular stress is mediated by apoptotic fragments of eIF4G translation initiation factor family members eIF4GI and p97/DAP5/NAT1. Journal of Biological Chemistry, in press.

Holcik, M., Gordon, B.W. and Korneluk, R.G. (2003) The IRES-mediated translation of anti-apoptotic protein XIAP is modulated by the heterogeneous nuclear ribonucleoproteins C (hnRNPC1/C2). Mol Cell Biol, 23, in press.

Holcik, M. (2002) The IAP proteins. Trends Genet, 18, 537-538.

Holcik, M. and Korneluk, R.G. (2001) XIAP, the guardian angel. Nat Rev Mol Cell Biol, 2, 550-556.

Holcik, M. and Korneluk, R.G. (2000) Functional Characterization of the X-Linked Inhibitor of Apoptosis (XIAP) Internal Ribosome Entry Site Element: Role of La Autoantigen in XIAP Translation. Mol Cell Biol, 20, 4648-4657.

Holcik, M., Sonenberg, N. and Korneluk, R.G. (2000) Internal ribosome initiation of translation and the control of cell death. Trends in Genetics, 16, 469-473.

Holcik, M., Yeh, C., Korneluk, R.G. and Chow, T. (2000) Translational upregulation of X-linked inhibitor of apoptosis (XIAP) increases resistance to radiation induced cell death. Oncogene, 19, 4174-4177.

Holcik, M., Lefebvre, C.A., Yeh, C., Chow, T. and Korneluk, R.G. (1999) A new internal-ribosome-entry-site motif potentiates XIAP-mediated cytoprotection. Nature Cell Biology, 1, 190-192.