Oncotarget

Research Papers:

Tumor suppressor p53 regulates insulin receptor (INSR) gene expression via direct binding to the INSR promoter

Rive Sarfstein and Haim Werner _

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Oncotarget. 2020; 11:2424-2437. https://doi.org/10.18632/oncotarget.27645

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Abstract

Rive Sarfstein1 and Haim Werner1,2

1 Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel

2 Yoran Institute for Human Genome Research, Tel Aviv University, Tel Aviv 69978, Israel

Correspondence to:

Haim Werner,email: hwerner@post.tau.ac.il

Keywords: insulin; insulin-like growth factor-1 (IGF1); insulin receptor; IGF1 receptor; p53

Received: April 14, 2020     Accepted: June 01, 2020     Published: June 23, 2020

ABSTRACT

A significant volume of clinical and epidemiological data provides support to the concept that insulin and the insulin receptor (INSR) have an important role in breast cancer. Tumor suppressor p53 is the most frequently mutated molecule in human cancer. The present study was aimed at evaluating the hypothesis that p53 governs the expression and activation of the INSR gene in breast cancer cells. In addition, the study was designed to investigate the mechanism of action of p53 in the context of INSR gene regulation. The availability of MCF7 breast cancer-derived cell lines with specific disruption of either the insulin-like growth factor-1 receptor (IGF1R) or INSR allowed us to address the impact of the IGF1R and INSR pathways on p53 expression. Data indicate that the INSR gene constitutes a target for p53 action. Wild-type p53 stimulated INSR promoter activity in control cells while disruption of endogenous IGF1R or INSR led to inhibition of promoter activity by p53. Mutant p53 strongly stimulated INSR promoter. Furthermore, p53 directly binds to the INSR promoter in cells with a disrupted IGF1R. Combined, our results identified complex functional and physical interactions between p53 and the INSR pathway. The implications of the p53-INSR interplay in breast cancer needs to be further investigated.


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