MTOR/miR-142-3p/PRAS40 Signaling Cascade is Critical for Tuberous Sclerosis Complex-associated Renal Cystogenesis

Overview

Journal Cell Mol Biol Lett

Publisher Biomed Central

Specialties Biochemistry
Cell Biology
Molecular Biology

Date 2024 Sep 28

PMID 39333852

Authors

Shuyun Zhao

Shuai Hao

Jiasheng Zhou

Xinran Chen

Tianhua Zhang

Zhaolai Qi

Ting Zhang

Sajid Jalal

Chuanxin Zhai

Lu Yin

Yufei Bo

Hongming Teng

Yue Wang

Dongyan Gao

Hongbing Zhang

Lin Huang

Affiliations

Soon will be listed here.

Abstract

Background: Patients with tuberous sclerosis complex (TSC) develop renal cysts and/or angiomyolipomas (AMLs) due to inactive mutations of either TSC1 or TSC2 and consequential mTOR hyperactivation. The molecular events between activated mTOR and renal cysts/AMLs are still largely unknown.

Methods: The mouse model of TSC-associated renal cysts were constructed by knocking out Tsc2 specifically in renal tubules (Tsc2; ksp-Cre). We further globally deleted PRAS40 in these mice to investigate the role of PRAS40. Tsc2 cells were used as mTOR activation model cells. Inhibition of DNA methylation was used to increase miR-142-3p expression to examine the effects of miR-142-3p on PRAS40 expression and TSC-associated renal cysts.

Results: PRAS40, a component of mTOR complex 1, was overexpressed in Tsc2-deleted cell lines and mouse kidneys (Tsc2; ksp-Cre), which was decreased by mTOR inhibition. mTOR stimulated PRAS40 expression through suppression of miR-142-3p expression. Unleashed PRAS40 was critical to the proliferation of Tsc2 cells and the renal cystogenesis of Tsc2; ksp-Cre mice. In contrast, inhibition of DNA methylation increased miR-142-3p expression, decreased PRAS40 expression, and hindered cell proliferation and renal cystogenesis.

Conclusions: Our data suggest that mTOR activation caused by TSC2 deletion increases PRAS40 expression through miR-142-3p repression. PRAS40 depletion or the pharmacological induction of miR-142-3p expression impaired TSC2 deficiency-associated renal cystogenesis. Therefore, harnessing mTOR/miR-142-3p/PRAS40 signaling cascade may mitigate hyperactivated mTOR-related diseases.

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