Section: Rotations

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

Rotation/Thesis Projects

1. Characterize the functional significance of the interaction of the ARF tumor suppressor and pro-oncogenic CtBP transcription co repressor.     ARF is a potent tumor suppressor that can work with p53 but also independent of p53 in mice and humans.  CtBP is an ARF interacting protein and transcription co-repressor that represses epithelial and apoptosis genes.  CtBP can mediate an epithelial-mesenchymal transition (EMT) important in metastasis and promote cell survival and cell motility.  CtBP is also activated by hypoxia through an internal dehydrogenase domain.  ARF promotes CtBP degradation and inactivation.  Several projects in the lab will investigate the biochemical mechanism of proteasome delivery of CtBP by ARF, the mechanism by which ARF and CtBP regulate cell motility and invasiveness in vitro, as well as the in vivo function of ARF/CtBP interaction for tumor suppression in a mouse model.
2. Identify and characterize the novel ubiquitin ligase domain of p300/CBP and determine its role in transcriptional coactivation and regulation of transcription factor stability.     p300/CBP are HAT/coactivators and ubiquitin ligases that promotes elongation of Ub chains on p53.  It does not harbor a canonical E3 domain, such as RING or hect.  Mutational structure/function analysis will be performed to precisely localize the E3 domain, to then allow its production in large quantities for NMR or X-ray crystallographic analysis.  Ultimately, the physiologic function of this domain will be studied in vivo in a knock-in mouse model.
3. Characterize the proteasome delivery of p53 via proteasome-interacting proteins.     p53 is regulated by ubiquitination and degradation.  Its degradation is tightly controlled at the proteasome by interacting proteins and regulatory subunits like hHR23 and S5a.  RNAi techniques will be used to explore the specific roles of these proteins in in vivo p53 regulation.  In vitro, a reconstituted in vitro degradation system will be used to assign the precise biochemical roles of proteasome regulators in p53 regulated degradation.

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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