Abstract

The goal of this proposal is to understand why the loss of p27kip1 expression is a strong prognostic indicator for tumor development in many types of human cancer. This proposal examines two alternative hypotheses: First, that the loss of p27 may accelerate cell proliferation making the cell refractory to the negative growth influences of the surrounding cells; or second, that the loss of p27 may eliminate oncogene-induced apoptosis by """"""""desensitizing"""""""" the cell to negative growth regulatory signals.
In Aim 1, these two models will be examined in the development of pituitary tumors in Rb+/- and Rb+/-;p27-/- mice.
Aim 2 will investigate the relationship between p27-deficiency and p53-mdm2-Arf induced apoptosis in the pituitary tumor mouse model, and in human breast and prostate tumor samples.
Aim 3 will characterize the growth, apoptosis and transformation properties of mouse embryonic fibroblasts derived from Rb-/-;p27-/- embryos. A 4th Aim is proposed in the supplementary information that is based on the recent finding of Adenocarcinomas in p107+/-;p130-/-;p27-/- mice. This section will extend the analysis of Rb+/-;p27-/- mice to other pocket protein/p27 combinations to determine how loss of p27 modulates their tumor suppressor properties.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA089563-05
Application #
6833487
Study Section
Cell Development and Function Integrated Review Group (CDF)
Program Officer
Yassin, Rihab R,
Project Start
2001-01-20
Project End
2006-12-31
Budget Start
2005-01-25
Budget End
2006-12-31
Support Year
5
Fiscal Year
2005
Total Cost
$351,731
Indirect Cost

  Institution

Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065

  Publications

Liu, Y; Raheja, R; Yeh, N et al. (2014) TRIM3, a tumor suppressor linked to regulation of p21(Waf1/Cip1.). Oncogene 33:308-15
Raheja, Radhika; Liu, Yuhui; Hukkelhoven, Ellen et al. (2014) The ability of TRIM3 to induce growth arrest depends on RING-dependent E3 ligase activity. Biochem J 458:537-45
Pérez-Sanz, J; Arluzea, J; Matorras, R et al. (2013) Increased number of multi-oocyte follicles (MOFs) in juvenile p27Kip1 mutant mice: potential role of granulosa cells. Hum Reprod 28:1023-30
Marchini, Sergio; Poynor, Elizabeth; Barakat, Richard R et al. (2012) The zinc finger gene ZIC2 has features of an oncogene and its overexpression correlates strongly with the clinical course of epithelial ovarian cancer. Clin Cancer Res 18:4313-24
Miller, Jeffrey P; Yeh, Nancy; Hofstetter, Christoph P et al. (2012) p27kip1 protein levels reflect a nexus of oncogenic signaling during cell transformation. J Biol Chem 287:19775-85
Hukkelhoven, Ellen; Liu, Yuhui; Yeh, Nancy et al. (2012) Tyrosine phosphorylation of the p21 cyclin-dependent kinase inhibitor facilitates the development of proneural glioma. J Biol Chem 287:38523-30
Ciznadija, Daniel; Zhu, Xin-Hua; Koff, Andrew (2011) Hdm2- and proteasome-dependent turnover limits p21 accumulation during S phase. Cell Cycle 10:2714-23
Ciznadija, Daniel; Liu, Yuhui; Pyonteck, Stephanie M et al. (2011) Cyclin D1 and cdk4 mediate development of neurologically destructive oligodendroglioma. Cancer Res 71:6174-83
See, W L; Miller, J P; Squatrito, M et al. (2010) Defective DNA double-strand break repair underlies enhanced tumorigenesis and chromosomal instability in p27-deficient mice with growth factor-induced oligodendrogliomas. Oncogene 29:1720-31
Miller, Jeffrey P; Yeh, Nancy; Vidal, Anxo et al. (2007) Interweaving the cell cycle machinery with cell differentiation. Cell Cycle 6:2932-8

Showing the most recent 10 out of 16 publications