Oncotarget: Tumor suppressor p53 regulates insulin receptor gene expression

June 23, 2020

Volume 11, Issue 25 of @Oncotarget reported that the present study was aimed at evaluating the hypothesis that p53 governs the expression and activation of the INSR gene in breast cancer cells.

The availability of MCF7 breast cancer-derived cell lines with specific disruption of either the insulin-like growth factor-1 receptor or INSR allowed us to address the impact of the IGF1R and INSR pathways on p53 expression.

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.

Dr. Haim Werner from Tel Aviv University said, "The insulin/insulin-like growth factors (IGFs) create a hormonal network responsible for the regulation of important physiological events throughout life."

"The insulin/insulin-like growth factors (IGFs) create a hormonal network responsible for the regulation of important physiological events throughout life"

- Dr. Haim Werner, Tel Aviv University
The classical view that emerged following the cloning and characterization of the INSR and IGF1R genes in the mid-1980s postulated that activation of INSR by insulin leads, predominantly, to metabolic activities.

One of the cardinal questions still in need of a biologically plausible rationalization is why the INSR and IGF1R, even though they share the majority of their downstream cytoplasmic targets and signaling pathways, are yet responsible for mediating distinct physiological and pathological activities.

Given the emerging evidence of proliferative and potentially anti-apoptotic actions of INSR, the authors investigated in the present paper the regulation of the INSR gene promoter by wild-type and mutant p53 in breast cancer cells.

Using cells with specific disruption of the INSR or IGF1R, the authors also assessed the effect of each one of these signaling pathways on p53 expression and activity.

The data indicate that: activation of p53 is negatively regulated by IGF1R, as indicated by the augmented phosphorylation of p53 in IGF1R-KD cells; p53 directly binds to the INSR promoter region in cells with a disrupted IGF1R; wild-type p53 represses INSR promoter activity in IGF1R-KD and INSR-KD cells while enhancing promoter activity in control cells; mutant p53 stimulates INSR promoter activity in breast cancer cells.

The Werner Research Team concluded in their OncotargetResearch Paper, "we have presented evidence that the INSR gene constitutes a downstream target for p53 action. Whereas wild-type p53 stimulated INSR promoter activity in control MCF7 cells, disruption of endogenous IGF1R or INSR led to inhibition of promoter activity by wild-type p53. Mutant, oncogenic versions of p53, for the most part, strongly stimulated INSR promoter. In addition, p53 exhibits direct binding to the INSR promoter region in cells with a disrupted IGF1R. Taken together, data presented here identifies complex functional and physical interactions between p53 and the INSR pathway. The clinical implications of this interplay in breast cancer needs to be critically assessed."
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DOI - https://doi.org/10.18632/oncotarget.27645

Full text - https://www.oncotarget.com/article/27645/text/

Correspondence to - Haim Werner - hwerner@post.tau.ac.il

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

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