We previously cloned p63, a p53 family member, and subsequently investigated its role in cancer. We were the first to identify p63 amplification and over expression in human squamous cell carcinoma and demonstrated that forced p63 expression led to increased proliferation and tumor growth. Moreover, we showed that WT p53 bound deltaNp63 leading to p63's caspase-dependent degradation. We then demonstrated that (Np63 associated and inhibited the B56alpha regulatory subunit of protein phosphatase 2A (PP2A), leading to inhibition of GSK3beta-mediated phosphorylation of beta-catenin, and in turn, nuclear accumulation of beta- catenin and dramatic activation of beta-catenin signaling. Recently, we found that p63 proteins undergo phosphorylation and degradation following exposure to DNA damaging agents. This revised proposal for renewal is now centered on further understanding the underlying function of p63 in response to the DNA damaging agent cisplatin. We discovered marked p63 degradation after cisplatin exposure accompanied by p53 stabilization. Moreover, we found an interesting correlation between p63 levels and cisplatin response in primary head and neck cancers. We hypothesize that p63 (like p53 and perhaps p73) is a critical determinant of the cellular response following DNA damage. We will explore putative phosphorylation sites on p63 that result in its degradation after cisplatin exposure 2) dissect the kinase cascade responsible for p63 phosphorylation 3) identify new p63 transcriptional targets after cisplatin exposure and modification and 4) define a consensus p63 cis binding site and differences in binding after modification. Thus, understanding the molecular mechanisms underlying this p63 response will lead to a deeper understanding of p63 function and could lead to improvements in current therapeutic approaches for human head and neck cancers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE013561-09
Application #
7658181
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Shirazi, Yasaman
Project Start
1999-12-01
Project End
2011-08-31
Budget Start
2009-09-01
Budget End
2011-08-31
Support Year
9
Fiscal Year
2009
Total Cost
$328,730
Indirect Cost
Name
Johns Hopkins University
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Huang, Yiping; Chuang, Alice Y; Ratovitski, Edward A (2011) Phospho-?Np63?/miR-885-3p axis in tumor cell life and cell death upon cisplatin exposure. Cell Cycle 10:3938-47
Sen, Tanusree; Sen, Nilkantha; Huang, Yiping et al. (2011) Tumor protein p63/nuclear factor ?B feedback loop in regulation of cell death. J Biol Chem 286:43204-13
Sen, Tanusree; Sen, Nilkantha; Brait, Mariana et al. (2011) DeltaNp63alpha confers tumor cell resistance to cisplatin through the AKT1 transcriptional regulation. Cancer Res 71:1167-76
Huang, Y; Chuang, A; Hao, H et al. (2011) Phospho-?Np63? is a key regulator of the cisplatin-induced microRNAome in cancer cells. Cell Death Differ 18:1220-30
Ratovitski, Edward A (2011) ?Np63?/IRF6 interplay activates NOS2 transcription and induces autophagy upon tobacco exposure. Arch Biochem Biophys 506:208-15
Chatterjee, Aditi; Chang, Xiaofei; Sen, Tanusree et al. (2010) Regulation of p53 family member isoform DeltaNp63alpha by the nuclear factor-kappaB targeting kinase IkappaB kinase beta. Cancer Res 70:1419-29
Huang, Yiping; Ratovitski, Edward A (2010) Phosphorylated TP63 induces transcription of RPN13, leading to NOS2 protein degradation. J Biol Chem 285:41422-31
Chatterjee, Aditi; Sen, Tanusree; Chang, Xiaofei et al. (2010) Yes-associated protein 1 regulates the stability of DeltaNp63alpha. Cell Cycle 9:162-7
Huang, Yiping; Chuang, Alice Y; Romano, Rose-Anne et al. (2010) Phospho-DeltaNp63alpha/NF-Y protein complex transcriptionally regulates DDIT3 expression in squamous cell carcinoma cells upon cisplatin exposure. Cell Cycle 9:328-38
Sen, Tanusree; Chang, Xiaofei; Sidransky, David et al. (2010) Regulation of ýýNp63ýý by NFýýýý. Cell Cycle 9:4841-7

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