The inability to enforce cell cycle arrests is one hallmark of cancer. The genetic and biochemical mechanisms that enforce these arrests are known as checkpoints, and are encoded by several of the most commonly mutated tumor suppressor genes such as p53 and p16INK4a. PTEN is one of the most commonly inactivated tumor suppressor genes in human cancer. We have previously demonstrated that PTEN plays a central role in enforcing cell size arrest during radiation-induced cell cycle arrest. The discover of this PTEN-dependent cell size checkpoint helped to explain the existence of dramatically enlarged cells in PTEN mutant flies and mice, and provided insight into the fact that inherited PTEN mutations cause a predisposition to hamartomas, which are characterized by enlarged cells. We hypothesize that loss of the cell size checkpoint contributes directly to tumorigenesis. In the first cycle of this grant, we made a number of observations directly related to the size checkpoint: (i) Like other checkpoints that are commonly defective in cancer cells, the PTEN- dependent cell size checkpoint is inducible by ionizing radiation and DNA-damaging chemotherapeutic drugs. (ii) The PTEN-dependent cell size checkpoint is Akt-independent;(iii) PTEN-dependent actin remodeling is required for cell size checkpoint control;(iv) Endogenous PTEN interacts at the membrane with a novel, PIP2-regulated actin remodeling complex;(v) Mutational inactivation of PTEN leads to activation of p53, suggesting the existence of crosstalk between the size checkpoint and the G1/G2 checkpoints. This first competitive renewal is designed to build on these advances to further evaluate the mechanistic basis and phenotypic consequences of the PTEN-dependent size checkpoint in human cells.
In Aim #1 we will determine if regulation of actin dynamics by PTEN is required for cell size checkpoint control.
In Aim #2 we propose to identify the composition and function of a PTEN-containing actin remodeling complex.
In Aim #3 we will determine if regulation of cell size checkpoint control is required for PTEN-mediated tumor suppression.
PTEN is commonly mutated in glioblastomas, endometrial carcinomas, melanomas, advanced prostate adenocarcinomas, and other tumor types. As such, it is one of the most commonly mutated tumor suppressor genes in human cancer. This grant focuses on characterizing a key function of PTEN in control of a DNA damage-induced cell size checkpoint. Identifying function(s) of PTEN in normal and neoplastic cells is critical for the eventual discovery of novel anticancer therapeutics that target PTEN-deficient cancer cells.
|Solomon, David A; Kim, Jung-Sik; Waldman, Todd (2014) Cohesin gene mutations in tumorigenesis: from discovery to clinical significance. BMB Rep 47:299-310|
|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|
|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|
|Vitolo, Michele I; Weiss, Michele B; Szmacinski, Marta et al. (2009) Deletion of PTEN promotes tumorigenic signaling, resistance to anoikis, and altered response to chemotherapeutic agents in human mammary epithelial cells. Cancer Res 69:8275-83|
|Solomon, David A; Kim, Jung-Sik; Jean, Walter et al. (2008) Conspirators in a capital crime: co-deletion of p18INK4c and p16INK4a/p14ARF/p15INK4b in glioblastoma multiforme. Cancer Res 68:8657-60|
Showing the most recent 10 out of 13 publications