Activation of PIP3 signaling by inactivating mutations in the PTEN tumor suppressor or activating mutations in the PIK3CA oncogene is found in a wide range of common human cancers. Though the biochemical details of PIP3 signal transduction are rapidly emerging, the phenotypic consequences of PIP3 pathway activation in human cancer cells remain less well defined. As such, the long-term goal of this project is to define the effects of PIP3 activation in human cancer cells. In our initial preliminary studies, we employed human somatic cell gene targeting to create isogenic sets of PTEN+/+ and PTEN-/- human cancer cell lines. Using these and related model systems, we found that PTEN controls a novel radiation-induced size checkpoint in human cells that is distinct and genetically separable from the radiation-induced, p53-dependent G1 and G2 checkpoints. To our knowledge, the existence of such a DNA damage-inducible size arrest has neither been postulated or demonstrated in any organism. Since the initial submission of this application we have employed human somatic cell gene targeting to create an isogenic set of PIK3CA gene targeted human cancer cells, and also created NIH3T3 cell lines that express wild-type, oncogenic, or inactive forms of PIK3CA. Using these systems we have obtained preliminary data suggesting that, like PTEN, the PIK3CA oncogene may be able to regulate size checkpoint function as well. In this application we propose three related specific aims to further pursue and extend these observations.
Aim #1 - Identify additional inducers of the PTEN-dependent size checkpoint.
Aim #2 - Demonstrate the presence of the PTEN-dependent size checkpoint in untransformed human cells.
Aim #3 - Characterize crosstalk between the radiation-induced, p53-dependent G1/G2 checkpoints and the radiation-induced, PTEN-dependent cell size checkpoint. Pursuit of these aims will enable us to further characterize the properties and mechanism(s) of a tumor suppressor gene-regulated, radiation-induced cell size checkpoint.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA115699-03
Application #
7417921
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Pelroy, Richard
Project Start
2006-05-11
Project End
2011-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
3
Fiscal Year
2008
Total Cost
$240,742
Indirect Cost
Name
Georgetown University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Walia, Vijay; Prickett, Todd D; Kim, Jung-Sik et al. (2014) Mutational and functional analysis of the tumor-suppressor PTPRD in human melanoma. Hum Mutat 35:1301-10
Solomon, David A; Kim, Jung-Sik; Waldman, Todd (2014) Cohesin gene mutations in tumorigenesis: from discovery to clinical significance. BMB Rep 47:299-310
Li, Hui-Fang; Keeton, Adam; Vitolo, Michele et al. (2011) A high-throughput screen with isogenic PTEN+/+ and PTEN-/- cells identifies CID1340132 as a novel compound that induces apoptosis in PTEN and PIK3CA mutant human cancer cells. J Biomol Screen 16:383-93
Kim, Jung-Sik; Xu, Xuehua; Li, Huifang et al. (2011) Mechanistic analysis of a DNA damage-induced, PTEN-dependent size checkpoint in human cells. Mol Cell Biol 31:2756-71
Duncan, Christopher G; Killela, Patrick J; Payne, Cathy A et al. (2010) Integrated genomic analyses identify ERRFI1 and TACC3 as glioblastoma-targeted genes. Oncotarget 1:265-77
Samuels, Yardena; Waldman, Todd (2010) Oncogenic mutations of PIK3CA in human cancers. Curr Top Microbiol Immunol 347:21-41
Michaud, Karine; Solomon, David A; Oermann, Eric et al. (2010) Pharmacologic inhibition of cyclin-dependent kinases 4 and 6 arrests the growth of glioblastoma multiforme intracranial xenografts. Cancer Res 70:3228-38
Lopez, Giselle Y; Reitman, Zachary J; Solomon, David et al. (2010) IDH1(R132) mutation identified in one human melanoma metastasis, but not correlated with metastases to the brain. Biochem Biophys Res Commun 398:585-7
Li, Hui-Fang; Kim, Jung-Sik; Waldman, Todd (2009) Radiation-induced Akt activation modulates radioresistance in human glioblastoma cells. Radiat Oncol 4:43
Solomon, David A; Kim, Jung-Sik; Yang, Xiaohong R et al. (2009) Lack of inherited mutations of PTPRD in familial melanoma and melanoma-astrocytoma syndrome. Pigment Cell Melanoma Res 22:489-91

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