c-Jun promotes cellular survival by suppression of PTEN
K Hettinger1, F Vikhanskaya, M K Poh
1Laboratory of Molecular Carcinogenesis, Division of Cellular and Molecular Research, National Cancer Centre, 11, Hospital Drive, Singapore 169610, Singapore.
Abstract:
Activation of c-Jun, a component of the AP-1 family of transcription factors, leads to either promotion or prevention of apoptosis. However, the molecular determinants of c-Jun-mediated cell survival are still unclear. We show here that inducible expression of c-Jun promotes cellular survival by negatively regulating the expression of the tumor-suppressor PTEN, resulting in the concomitant activation of the Akt survival pathway. Consistently, c-jun-/- fibroblasts, which are sensitive to nutrient deprivation, and human cell lines in which c-Jun expression is silenced, express elevated levels of PTEN. siRNA-mediated silencing of PTEN resulted in the reduction of cell-death owing to c-Jun deficiency. c-Jun was found to suppress PTEN expression by binding to a variant AP-1 site found in the 5' upstream sequences of PTEN promoter. Finally, an inverse correlation between c-Jun and PTEN levels was apparent in a panel of human tumor cell lines, independent of their p53 status. Together, the data demonstrate that c-Jun contributes to the promotion of cellular survival by regulating the expression of PTEN.
Insights
The transcription factor c-Jun promotes cell survival by reducing PTEN expression, activating the Akt pathway. This finding clarifies c-Jun
Area of Science:
- Molecular Biology
- Cellular Biology
- Cancer Research
Background:
- The transcription factor c-Jun (a component of the AP-1 family) has a dual role in apoptosis, either promoting or preventing it.
- The precise molecular mechanisms underlying c-Jun's role in promoting cell survival remain incompletely understood.
Purpose of the Study:
- To elucidate the molecular determinants of c-Jun-mediated cell survival.
- To investigate the relationship between c-Jun, PTEN, and the Akt survival pathway.
Main Methods:
- Inducible expression of c-Jun in cell lines.
- Analysis of PTEN and Akt pathway activation.
- siRNA-mediated silencing of PTEN.
- Chromatin immunoprecipitation to assess c-Jun binding to the PTEN promoter.
- Examination of c-Jun and PTEN levels in human tumor cell lines.
Main Results:
- Inducible c-Jun expression promotes cell survival by downregulating tumor suppressor PTEN, leading to Akt pathway activation.
- Fibroblasts deficient in c-Jun (c-jun-/-) and human cells with silenced c-Jun exhibit elevated PTEN levels and sensitivity to nutrient deprivation.
- Silencing PTEN rescues cell death associated with c-Jun deficiency.
- c-Jun directly suppresses PTEN expression by binding to a variant AP-1 site in the PTEN promoter.
- An inverse correlation between c-Jun and PTEN levels is observed in human tumor cell lines, irrespective of p53 status.
Conclusions:
- c-Jun promotes cellular survival through the negative regulation of PTEN expression.
- This regulatory mechanism involves the direct binding of c-Jun to the PTEN promoter, leading to the activation of the Akt survival pathway.
- The findings highlight a novel role for c-Jun in cancer cell survival by modulating the PTEN/Akt axis.
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