DEPTOR is a direct p53 target that suppresses cell growth and chemosensitivity

Danrui Cui,Longyuan Gong,Xiufang Xiong,Linchen Wang,Xiaoyu Chen,Xiaoqing Dai,Yongchao Zhao

doi:10.1038/s41419-020-03185-3

Abstract

DEP-domain containing mTOR-interacting protein (DEPTOR), a natural mTOR inhibitor, has essential roles in several processes, including cell growth, metabolism, apoptosis, and immunity. DEPTOR expression has been shown to be diversely controlled at transcriptional levels in cell- and context-specific manners. However, whether there is a general mechanism for the regulation of DEPTOR expression remains largely unknown. Here, we report that DEPTOR is a downstream target of the tumor suppressor, p53, whose activity is positively correlated with DEPTOR expression both in vitro in cell cultures and in vivo in mouse tissues. Mechanistically, p53 directly binds to the DEPTOR promoter and transactivates its expression. Depletion of the p53-binding site on the DEPTOR promoter by CRISPR-Cas9 technology decreases DEPTOR expression and promotes cell proliferation and survival by activating AKT signaling. Importantly, inhibition of AKT by small molecular inhibitors or genetic knockdown abrogates the induction of cell growth and survival induced by deletion of the p53-binding region on the DEPTOR promoter. Furthermore, p53, upon activation by the genotoxic agent doxorubicin, induces DEPTOR expression, leading to cancer cell resistance to doxorubicin. Together, DEPTOR is a direct p53 downstream target and contributes to p53-mediated inhibition of cell proliferation, survival, and chemosensitivity.

Highlights

Mammalian target of rapamycin, an evolutionarily conserved serine/threonine protein kinase, has pivotal roles in the coordination of cell responses to various stimuli and serves as a central regulator of cell proliferation, survival, and autophagy[1,2,3]
We demonstrated that p53 directly binds to the DEPTOR promoter and activates its transcription. p53-mediated DEPTOR expression suppressed cell proliferation and survival by inhibiting AKT activity in unstressed conditions
DEPTOR expression is dependent on the presence of p53 in cancer cells and mouse tissues p53 has an important role in the regulation of mTORC1 activity through the induction of PTEN, TSC2, and REDD118,19

Summary

Introduction

Mammalian target of rapamycin (mTOR), an evolutionarily conserved serine/threonine protein kinase, has pivotal roles in the coordination of cell responses to various stimuli and serves as a central regulator of cell proliferation, survival, and autophagy[1,2,3]. It is well known that mTORC1 is mainly involved in the regulation of protein translation, cell growth, and usually acts as a tumor suppressor, by inhibiting mTOR, to suppress cell growth, and survival via inactivation of AKT5,6. In specific cancer types, such as multiple myeloma and T-cell acute lymphoblastic leukemia, DEPTOR exhibits oncogenic properties by activating. Given that DEPTOR expression is highly cell-specific and context-dependent[7], its transcriptional regulation likely contributes to the complexity of its roles in tumorigenesis.

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