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Associate Professor, Biochemistry Associate Professor, Fels Institute for Cancer Research and Molecular Biology Telephone: 215-707-7416 Fax: 215-707-2805 Email: xavier@temple.edu
Department of BiochemistryFels Institute for Cancer Research and Molecular Biology
Cell cycle control in mammalian cells. Role of cyclins, cyclin dependent kinases (CDKs) and tumor suppressor genes: Cancer and HIV. Research in my laboratory focuses on the molecular mechanisms that govern the cell cycle of normal and malignant eukaryotic cells and the control of gene expression. Eukaryotic cells have evolved to respond to a large array of growth promoting and inhibiting signals, which are eventually integrated by a conserved protein engine consisting of distinct cyclin/CDKs. CDKs are activated and required at specific stages of the cell cycle (reviewed by Graña and Reddy 1995; Graña et al., 1998). I am interested in how these regulatory pathways are disrupted in cancer cells as well as in cells transformed by small DNA viruses or infected by HIV (reviewed in Graña et al., 1998, Garriga and Graña 2004). Work in this laboratory has been funded by grants from NIGMS, NCI, NIAIDs, and W.W. Smith Charitable Trust.
One initial focus of this laboratory was the characterization of p130, a protein structurally and functionally related to the product of the retinoblastoma susceptibility gene (reviewed in Mayol and Graña, 1997; 1998; Graña et al., 1998). We have shown that the phosphorylation state of p130 is regulated in a cell cycle dependent manner by CDKs and PP2A (Mayol et al., 1995; Parreño et al., 2000 and 2001, Calbo et al., 2002; Garriga et al., 2004) and that specific phosphorylated forms of p130 interact with E2F-4 and E2F-1 (Mayol et al., 1996; Calbo et al., 2002). In addition, we have investigated the relationship between the protein levels and phosphorylation status of pocket proteins (Mayol et al., 1996; Garriga et al., 1998a) showing that p130 protein levels are regulated by the SCFSKP2 ubiquitin ligase (Bhattacharya et al., 2003). Recently, our focus has expanded to studies dealing with the coordinated regulation of the three members of the retinoblastoma family of proteins by CDKs and phosphatases in response to a variety of signals (Calbo et al., 2002; Garriga et al., 2004). We have shown that certain serum starved immortal and tumor cells enter the cell cycle in the absence of mitogens following ectopic expression of G1 cyclins (Calbo et al., 2002). We are currently studying the minimal molecular steps required to induce a variety of transformed characteristics in primary normal human cells.
The other primary area of research in this lab deals with the functional characterization of CDK9 (formerly named, PITALRE)(Graña et al., 1994; Garriga et al., 1996a and Garriga et al., 1996b). Following identification of CDK9 as a subunit of the Positive Transcription Elongation Factor b (P-TEFb) and HIV tat associated kinase by others, we demonstrated that cyclin T1, one of the three cyclins that bind to and activate CDK9, is upregulated during T-cell activation. Upregulation of cyclin T1 correlates with phosphorylation of RNA pol II in vivo and HIV-1 replication (Garriga et al., 1998b). Subsequently, we have characterized the signaling pathways and mechanisms responsible for cyclin T1 upregulation during T cell activation (Marshall et al., 2005). Moreover, we have recently found that, although CDK9/cyclin T1 complexes are targeted by the SCFSKP2 ubiquitin ligase, this association does not seem to regulate CDK9 expression during the cell cycle, but may regulate CDK9 transcriptional function (Garriga et al., 2003). Our current goals are (a) to unravel the function of T-type cyclin/CDK9 complexes during T-cell activation, which is relevant to the development of novel HIV therapeutic approaches; and (b) to identify CDK9 dependent genes.
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Xavier Grana, PhD 