MOLECULAR MECHANISMS THAT LEAD TO THE DEVELOPMENT OF CARDIAC HYPERTROPHY AND FAILURE

We have previously reported a unique role for RasGTPase-activating protein (RasGAP) in the development of cardiac hypertrophy. Mainly, we discovered that it is involved in the enhancement of Cdk7 and RNA polymerase II activities in cardiac cells, a mechanism that leads to the increase in total RNA and protein in the cell, which is the hallmark of hypertrophy. Using the yeast two-hybrid system we have next shown that RasGAP interacts with the cytoskeletal protein filmain. This interaction is necessary for cytoskeletal integrity and cell survival and regulates Cdk7 and pol II expression. Recent studies form our and others laboratories have recently identified a major role for Cdk7 and RNA polymerase II incell survival, thus, potentially linking the hypertrophy pathway to that of cell survival. Current work in the laboratory aims to further delineate the role of RasGAP in cell survival and its relationship to hypertrophy both in cultured cardiac myocytes and in transgenic and knockout mouse models.

A second project in the lab involves the integrin-linked kinase (ILK). Previously, using subtractive hybridization, we have identified more than 50 genes, including ILK, that are upregulated during cardiac hypertrophy. Using the yeast two-hybrid system we have then identified the Lim-only protein as a partner for ILK. We then discovered that ILK regulates the expression of the cardiac transcription factor GATA4. We currently are in the process of learning more about the function of ILK and its interacting proteins in the heart. Again, this will involve cultured cardiac myocytes and transgenic and knockout mouse models.

Representative Publications:

MacLellan WR, Xiao G, Abdellatif M, Schneider MD. A novel Rb- and p300-binding protein inhibits transactivation by MyoD. Mol Cell Biol. 2000 Dec;20(23):8903-15. PubMed Citation

Abdellatif M. Leading the way using microarray: a more comprehensive approach for discovery of gene expression patterns. Circ Res. 2000 May 12;86(9):919-20. PubMed Citation

Johnatty SE, Dyck JR, Michael LH, Olson EN, Abdellatif M. Identification of genes regulated during mechanical load-induced cardiac hypertrophy. J Mol Cell Cardiol. 2000 May;32(5):805-15. PubMed Citation

Akli S, Zhan S, Abdellatif M, Schneider MD. E1A can provoke G1 exit that is refractory to p21 and independent of activating cdk2. Circ Res. 1999 Aug 20;85(4):319-28. PubMed Citation

Abdellatif M, Packer SE, Michael LH, Zhang D, Charng MJ, Schneider MD. A Ras-dependent pathway regulates RNA polymerase II phosphorylation in cardiac myocytes: implications for cardiac hypertrophy. Mol Cell Biol. 1998 Nov;18(11):6729-36. PubMed Citation