Activation of p53-dependent growth suppression in human cells by mutations in PTEN or PIK3CA.

Activation of p53-dependent growth suppression in human cells by mutations in PTEN or PIK3CA. Research Abstract Details 

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Activation of p53-dependent growth suppression in human cells by mutations in PTEN or PIK3CA. Abstract Text:

Jung-Sik Kim,Carolyn Lee,Challice L Bonifant,Habtom Ressom,Todd Waldman,

In an effort to identify genes whose expression is regulated by activated phosphatidylinositol 3-kinase (PI3K) signaling, we performed microarray analysis and subsequent quantitative reverse transcription-PCR on an isogenic set of PTEN gene-targeted human cancer cells. Numerous p53 effectors were upregulated following PTEN deletion, including p21, GDF15, PIG3, NOXA, and PLK2. Stable depletion of p53 led to reversion of the gene expression program. Western blots revealed that p53 was stabilized in HCT116 PTEN(-/-) cells via an Akt1-dependent and p14(ARF)-independent mechanism. Stable depletion of PTEN in untransformed human fibroblasts and epithelial cells also led to upregulation of p53 and senescence-like growth arrest. Simultaneous depletion of p53 rescued this phenotype, enabling PTEN-depleted cells to continue proliferating. Next, we tested whether oncogenic PIK3CA, like inactivated PTEN, could activate p53. Retroviral expression of oncogenic human PIK3CA in MCF10A cells led to activation of p53 and upregulation of p53-regulated genes. Stable depletion of p53 reversed these PIK3CA-induced expression changes and synergized with oncogenic PIK3CA in inducing anchorage-independent growth. Finally, targeted deletion of an endogenous allele of oncogenic, but not wild-type, PIK3CA in a human cancer cell line led to a reduction in p53 levels and a decrease in the expression of p53-regulated genes. These studies demonstrate that activation of PI3K signaling by mutations in PTEN or PIK3CA can lead to activation of p53-mediated growth suppression in human cells, indicating that p53 can function as a brake on phosphatidylinositol (3,4,5)-triphosphate-induced mitogenesis during human cancer pathogenesis.

Activation of p53-dependent growth suppression in human cells by mutations in PTEN or PIK3CA. Publishing Authors By Initials

JS Kim,C Lee,CL Bonifant,H Ressom,T Waldman,

For similar proteins: dna-binding proteins: tumor suppressor protein p53 research abstracts see: proteins: dna-binding proteins: tumor suppressor protein p53 research

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MEDLINE DATE:

Activation of p53-dependent growth suppression in human cells by mutations in PTEN or PIK3CA. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Molecular and cellular biology

VOLUME: 27

Page Numbers: 662-77

Journal Abbreviation: Mol. Cell. Biol.

ISSN: 0270-7306

DAY: 23

MONTH: 10

YEAR: 2006

Activation of p53-dependent growth suppression in human cells by mutations in PTEN or PIK3CA. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 8109087

Activation of p53-dependent growth suppression in human cells by mutations in PTEN or PIK3CA. Keywords Mesh Terms:

KEYWORDS: Tumor Suppressor Protein p53

MESH TERMS: metabolism

Chemical & Substance for Abstract: Activation of p53-dependent growth suppression in human cells by mutations in PTEN or PIK3CA. Information

Substance Name: PTEN Phosphohydrolase

Registry Number: EC 3.1.3.67

Grant and Affiliation Information for Activation of p53-dependent growth suppression in human cells by mutations in PTEN or PIK3CA.

AFFILIATION: Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, 3970 Reservoir Road NW, NRB E304, Washington, DC 20057, USA.

Country: United States

AGENCY: United States NCI

GRANT: T32 CA 009686

ACRONYM: CA

MEDLINETA: Mol Cell Biol

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ACCESSION NUMBER: GSE6263

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