Abstract

p53 is the most commonly mutated gene in human cancer. Loss of p53-dependent apoptosis contributes to tumorigenesis, tumor progression and chemotherapeutic drug resistance. Tumor-derived mutants of p53 lose the properties of DNA binding, transactivation, apoptosis induction and suppression of cancer colony growth. The applicant has investigated the role of p53 as a determinant of chemosensitivity and identified an ovarian teratocarcinoma cell line where targeted degradation of p53 led to 100- to 1000-fold decrease in chemosensitivity in multiple clones. Using subtractive hybridization he has identified KILLER/DR5 as a DNA damage-inducible apoptosis-inducing p53-regulated death receptor gene. KILLER/DR5 expression appears to be decreased in human cancer cell lines that do not express wild-type p53. KILLER/DR5 maps to human chromosome 8p21, a location where tumor suppressors are believed to reside in several human tumor types include head and neck and prostate cancer. We plan to investigate the role of KILLER/DR5 as a tumor suppressor gene and loss of function of a head and neck tumor-derived truncating mutant that we have identified. These experiments could lead to novel strategies for anti-cancer therapy.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA075454-01A1
Application #
2700764
Study Section
Pathology B Study Section (PTHB)
Program Officer
Johnson, George S
Project Start
1998-09-14
Project End
2002-06-30
Budget Start
1998-09-14
Budget End
1999-06-30
Support Year
1
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

Wang, Shulin; Mintz, Akiva; Mochizuki, Kenjiro et al. (2007) Multimodality optical imaging and 18F-FDG uptake in wild-type p53-containing and p53-null human colon tumor xenografts. Cancer Biol Ther 6:1649-53
Wang, Shulin; El-Deiry, Wafik S (2006) p73 or p53 directly regulates human p53 transcription to maintain cell cycle checkpoints. Cancer Res 66:6982-9
Finnberg, Niklas; Gruber, Joshua J; Fei, Peiwen et al. (2005) DR5 knockout mice are compromised in radiation-induced apoptosis. Mol Cell Biol 25:2000-13
Wang, Shulin; El-Deiry, Wafik S (2004) Inducible silencing of KILLER/DR5 in vivo promotes bioluminescent colon tumor xenograft growth and confers resistance to chemotherapeutic agent 5-fluorouracil. Cancer Res 64:6666-72
Fei, Peiwen; Wang, Wenge; Kim, Seok-hyun et al. (2004) Bnip3L is induced by p53 under hypoxia, and its knockdown promotes tumor growth. Cancer Cell 6:597-609
Burns, Timothy F; El-Deiry, Wafik S (2003) Microarray analysis of p53 target gene expression patterns in the spleen and thymus in response to ionizing radiation. Cancer Biol Ther 2:431-43
Wang, Shulin; El-Deiry, Wafik S (2003) Requirement of p53 targets in chemosensitization of colonic carcinoma to death ligand therapy. Proc Natl Acad Sci U S A 100:15095-100
Sax, Joanna K; Stoddard, Alex; Murphy, Maureen E et al. (2003) Microarray expression profiling of p53-dependent transcriptional changes in an immortalized mouse embryo fibroblast cell line. Cancer Biol Ther 2:416-30
Burns, T F; Bernhard, E J; El-Deiry, W S (2001) Tissue specific expression of p53 target genes suggests a key role for KILLER/DR5 in p53-dependent apoptosis in vivo. Oncogene 20:4601-12
McDonald 3rd, E R; Chui, P C; Martelli, P F et al. (2001) Death domain mutagenesis of KILLER/DR5 reveals residues critical for apoptotic signaling. J Biol Chem 276:14939-45

Showing the most recent 10 out of 13 publications