p21WAF1/CIP1 protein is a critical p53 transcriptional target, which is required for cell cycle arrest after ionizing radiation. The development of histiocytic sarcomas, hemangiomas/hemangiosarcomas and B cell lymphomas in p21 -/- mice suggests the importance of p21 in cancer. Loss of p21 also increases Adenomatous Polyposis Coil initiated gastrointestinal tumors, increases chemical induced skin carcinoma and cooperates with loss of other tumor suppressors like Rb and p18. p21 has also been shown to play an important role in autoimmunity and stem cell repopulation. It is therefore critical that we understand the regulatory pathways which control p21 protein levels. Although numerous studies have investigated the importance of transcriptional regulation in p21 function, the role of post translational regulation remains less clear. The regulation of p21 proteins levels by post translational mechanisms is the focus of this grant. In preliminary results we describe the identification of a novel protein WISp39 (p39) which stabilizes p21 protein levels. WISp39 acts like an adaptor protein which recruits Hsp90 (via its C-terminal TPR domain) in order to stabilize p21. We propose to investigate in detail the role of Hsp90 binding TPR proteins in regulating p21 stability and function. We will analyze the molecular and functional characteristics of p39 mediated p21 stability using both tissue culture models and whole animal models. By generating p39 -/- mice we will evaluate the functional consequences of p39 on p21 stability in checkpoint control, and tumor generation and development in a whole animal model. Finally we will study the effect of non-ubiquitinated p21 on cell cycle and the cellular response to DNA damage.
| Howell, Michael; Brickner, Howard; Delorme-Walker, Violaine D et al. (2015) WISp39 binds phosphorylated Coronin 1B to regulate Arp2/3 localization and Cofilin-dependent motility. J Cell Biol 208:961-74 |
| Panopoulos, Andreas; Howell, Michael; Fotedar, Rati et al. (2011) Glioblastoma motility occurs in the absence of actin polymer. Mol Biol Cell 22:2212-20 |
| Kim, J A; Lee, J; Margolis, R L et al. (2010) SP600125 suppresses Cdk1 and induces endoreplication directly from G2 phase, independent of JNK inhibition. Oncogene 29:1702-16 |
| Lee, Jinho; Kim, Jin Ah; Margolis, Robert L et al. (2010) Substrate degradation by the anaphase promoting complex occurs during mitotic slippage. Cell Cycle 9:1792-801 |
| Lee, Jinho; Kim, Jin Ah; Barbier, Valerie et al. (2009) DNA damage triggers p21WAF1-dependent Emi1 down-regulation that maintains G2 arrest. Mol Biol Cell 20:1891-902 |
