Section: Research

Steven Grossman, Ph.D.,M.D.

Academic Role: Associate Professor

Faculty Appointment(s) In:
   Cancer Biology
   Hematology/Oncology
   Medicine

Other Affiliation(s):
   Interdisciplinary Graduate Program
   Program in Immunology and Virology

Protein stability and cancer

           The formation and progression of human cancers is ultimately regulated by the abundance and activity of both oncogenic and tumor suppressor proteins.  Both genetic (i.e. mutational) and epigenetic mechanisms play a role in activating oncogenes and inactivating tumor suppressor proteins.  Our laboratory studies one aspect of the many epigenetic mechanisms at play in tumor initiation and progression-namely the regulation of protein abundance and activity through regulated ubiquitination and proteasome degradation.       

            The ubiquitin system tags proteins for destruction by the proteasome through covalent addition of the 8 kD ubiquitin polypeptide to lysine residues in target proteins.  An elaborate enzyme cascade consisting of three enzymes—E1, E2 and E3 regulate this process.  We are examining the mechanisms that regulate degradation of critical tumor suppressor proteins, such as the prototypical tumor suppressor, p53, as well as other regulators of cell growth and apoptosis, such as E2F.

            Previously we have shown that extension of ubiquitin chains on p53 is regulated by a novel and surprising ubiquitin enzyme—the coactivator/HAT p300 (Grossman et al, 2003).  Our recent data indicates additional steps in the regulation of p53 turnover occur after ubiquitination and prior to proteasome degradation (Brignone et al, 2004), where hHR23 proteins determine whether ubiquitinated p53 is degraded, or not.  Moreover, our data indicates an E3 ubiquitin ligase, MDM2, is a critical component in the ability of the proteasome to recognize its substrate, via a novel interaction we have discovered between MDM2 with hHR23 proteins (Brignone et al, 2004). 

We have recently shown that by RNAi techniques that both p300 and CBP contribute to p53 polyubiquitination and also show individual differences in their regulation of p53-dependent transcription, apoptosis, and p53 acetylation.  The p300/CBP E3 domain is novel and centered in the N-terminus.  A key goal is to isolate and structurally study this novel E3 domain.  Differences in p300 and CBP activity at p53 target promoters is also under study using chromatin IP techniques.

A more recent project in the lab has characterized another means by which protein stability and cancer biology are linked.  The ARF tumor suppressor binds to the pro-oncogenic CtBP repressor and targets it for proteasome degradation without affecting its ubiquitination.  CtBP can mediate cell motility, survival signaling, and the epithelial-mesenchymal transition.  We have shown that ARF can suppress cell motility and invasiveness caused by CtBP.  The mechanism of ARF-induced degradation of CtBP may involve direct proteasome delivery via an ARF interaction with a proteasome subunit.  This hypothesis is being tested in a novel in vitro degradation system for CtBP.  In addition, the in vivo function of ARF/CtBP interaction is being tested in a mouse knock-in model.

Office: LRB 419
Phone: 856-6423 or Clinic 6-3933
E-mail: Steven.Grossman@umassmed.edu
Keywords: Cell Biology, Gene Expression, Chemical Biology

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