PTEN and p53 are the most frequently mutated tumor suppressors in human cancer, including gliomas. Recent evidence shows that wild-type PTEN and wild-type p53 (wt-p53) enhance each other's tumor suppressive functions. Wt-p53 induces PTEN gene transcription and wt-PTEN protects wt-p53 protein from degradation. We recently found, for the first time, that PTEN has unexpected tumor promoting properties in some glioma cells and tumor xenografts. We have preliminary evidence that PTEN acquires these unexpected tumor promoting properties by enhancing the half-life and oncogenic effects of gain-of-function p53 mutants (mut-p53). Based on these findings, we formulate the following novel hypothesis: PTEN tumor suppressor can exhibit tumor promoting properties in the setting of gain-of-function mut-p53. Therefore, therapeutic strategies that aim at restoring PTEN expression or function could lead to varying effects that depend on the mutational status of p53. To test this hypothesis and its prognostic, mechanistic, functional and therapeutic implications, we propose the following studies:
In aim #1, we will use a large number of banked human glioblastoma specimens to determine the association between the combined PTEN/p53 mutational status and clinical outcome.
In aim #2, we will investigate the mechanism through which PTEN regulates mut-p53 protein levels and function.
In aim #3, we will assess the in vivo effects of restoring PTEN to glioma tumors with varying p53 mutational status.
In aim #4, we will determine if small molecule modulators of p53 can reverse the tumor promoting effects of PTEN in mut-p53 cells and tumors. The results from all aims will be assessed for their consistency with the hypothesis. Successful completion of the studies proposed in this application would: 1) establish the combined PTEN/p53 status as a prognostic parameter (aim 1), 2) uncover previously unknown mechanistic and functional interactions between PTEN and mut-p53 (aim 2), 3) determine conditions and strategies for a successful therapeutic restoration of PTEN (aim 3), and 4) have important clinical implications for the use of small molecule modulators of p53 by identifying a subset of tumors that are more sensitive to these drugs and providing a rationale for their combination with PTEN restoration (aim 4).

Public Health Relevance

We recently discovered that the tumor suppressor PTEN can have surprising tumor promoting properties. We have evidence that these unexpected properties depend on mutations of the tumor suppressor p53. We propose to study the interactions between PTEN and p53 mutations. We also propose to determine the conditions and test new strategies for successful tumor suppressor restoration to human tumors. The findings will have important implications on determining patient prognosis and developing new therapies against human cancers.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Watson, Joanna M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Virginia
Schools of Medicine
United States
Zip Code
Gonzalez, Phillippe P; Kim, Jungeun; Galvao, Rui Pedro et al. (2018) p53 and NF 1 loss plays distinct but complementary roles in glioma initiation and progression. Glia 66:999-1015
Zhang, Ying; Dube, Collin; Gibert Jr, Myron et al. (2018) The p53 Pathway in Glioblastoma. Cancers (Basel) 10:
Zhang, Ying; Cruickshanks, Nichola; Yuan, Fang et al. (2017) Targetable T-type Calcium Channels Drive Glioblastoma. Cancer Res 77:3479-3490
Feng, Chenzhuo; Zhang, Ying; Yin, Jinbo et al. (2014) Regulatory factor X1 is a new tumor suppressive transcription factor that acts via direct downregulation of CD44 in glioblastoma. Neuro Oncol 16:1078-85
Zhang, Y; Kim, J; Mueller, A C et al. (2014) Multiple receptor tyrosine kinases converge on microRNA-134 to control KRAS, STAT5B, and glioblastoma. Cell Death Differ 21:720-34
Zhang, Ying; Schiff, David; Park, Deric et al. (2014) MicroRNA-608 and microRNA-34a regulate chordoma malignancy by targeting EGFR, Bcl-xL and MET. PLoS One 9:e91546
Kim, Jungeun; Zhang, Ying; Skalski, Michael et al. (2014) microRNA-148a is a prognostic oncomiR that targets MIG6 and BIM to regulate EGFR and apoptosis in glioblastoma. Cancer Res 74:1541-53
Guessous, Fadila; Alvarado-Velez, Melissa; Marcinkiewicz, Lukasz et al. (2013) Oncogenic effects of miR-10b in glioblastoma stem cells. J Neurooncol 112:153-63
Kofman, Alexander V; Letson, Christopher; Dupart, Evan et al. (2013) The p53-microRNA-34a axis regulates cellular entry receptors for tumor-associated human herpes viruses. Med Hypotheses 81:62-7
Zhang, Ying; Farenholtz, Kaitlyn E; Yang, Yanzhi et al. (2013) Hepatocyte growth factor sensitizes brain tumors to c-MET kinase inhibition. Clin Cancer Res 19:1433-44

Showing the most recent 10 out of 20 publications