Inactivation of tumor suppressor genes or their protein products is important in the etiology of human cancer. p53 protein can be inactivated by interaction with viral or cellular proteins. Bdp/53BP2 is a protein which interacts with Bcl-2 and the DNA binding domain of p53. The broad long-term objectives of this proposal are to study the function of Bbp/53BP2 and determine the biological relevance of the interaction between p53 and Bbp/53BP2. The major hypothesis of this proposal is that Bbp/53BP2 affects the function of p53 by directly interacting with the DNA binding domain of p53 and preventing normal p53 function or localization.
The specific aims of this proposal are designed to test this hypothesis. (1) Determine if regulated expression of Bbp/53BP2 perturbs cellular physiology through interaction with p53. They will construct cells with regulated Bbp/53BP2 expression and study physiological effects upon expression of Bbp/53BP2. (2) Determine if Bbp/53BP2 expression can modulate p53 transactivation or induction of apoptosis. The effects of coexpressing Bbp/53BP2 and p53 will be studied in p53 transactivation and apoptosis assays. (3) Determine the relationship between p53 and Bbp/53BP2 subcellular localization. We will examine the ability of Bbp/53BP2 and p53 to coimmunoprecipitate and colocalize in various normal and malignant cell lines and tissues. The effects of overexpression of Bcl-2, as a potential antagonist of the interaction between Bbp/53BP2 and p53 will be investigated.
| Kampa, Kerstin M; Acoba, Jared D; Chen, Dexi et al. (2009) Apoptosis-stimulating protein of p53 (ASPP2) heterozygous mice are tumor-prone and have attenuated cellular damage-response thresholds. Proc Natl Acad Sci U S A 106:4390-5 |
| Zhu, Zhiyi; Ramos, Jason; Kampa, Kerstin et al. (2005) Control of ASPP2/(53BP2L) protein levels by proteasomal degradation modulates p53 apoptotic function. J Biol Chem 280:34473-80 |
| Qian, Hua; Wang, Ting; Naumovski, Louie et al. (2002) Groups of p53 target genes involved in specific p53 downstream effects cluster into different classes of DNA binding sites. Oncogene 21:7901-11 |
| Ao, Y; Rohde, L H; Naumovski, L (2001) p53-interacting protein 53BP2 inhibits clonogenic survival and sensitizes cells to doxorubicin but not paclitaxel-induced apoptosis. Oncogene 20:2720-5 |
| Lopez, C D; Ao, Y; Rohde, L H et al. (2000) Proapoptotic p53-interacting protein 53BP2 is induced by UV irradiation but suppressed by p53. Mol Cell Biol 20:8018-25 |
