DEPTOR is a direct p53 target that suppresses cell growth and chemosensitivity
Danrui Cui1,2, Xiaoqing Dai1,2, Longyuan Gong1,2
1Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
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.
Insights
The tumor suppressor p53 directly regulates DEP-domain containing mTOR-interacting protein (DEPTOR) expression. This p53-DEPTOR interaction influences cell growth, survival, and chemotherapy resistance.
Area of Science:
- Molecular Biology
- Cancer Biology
- Cell Signaling
Background:
- DEP-domain containing mTOR-interacting protein (DEPTOR) is a key mTOR inhibitor involved in cell growth, metabolism, apoptosis, and immunity.
- DEPTOR expression is regulated transcriptionally in a context-dependent manner, but a general regulatory mechanism remains unclear.
Purpose of the Study:
- To investigate the general mechanism regulating DEPTOR expression.
- To determine the relationship between the tumor suppressor p53 and DEPTOR expression.
Main Methods:
- In vitro cell culture and in vivo mouse tissue studies.
- Chromatin immunoprecipitation (ChIP) assays to assess p53 binding to the DEPTOR promoter.
- CRISPR-Cas9 technology to deplete the p53-binding site on the DEPTOR promoter.
- AKT signaling pathway analysis using small molecular inhibitors and genetic knockdown.
Main Results:
- p53 directly binds to the DEPTOR promoter and activates its transcription, showing a positive correlation between p53 activity and DEPTOR expression.
- Deletion of the p53-binding site on the DEPTOR promoter reduces DEPTOR levels, enhances cell proliferation and survival via AKT activation.
- Inhibition of AKT signaling abrogates the pro-survival effects of DEPTOR expression changes.
- Activated p53 induces DEPTOR expression, conferring cancer cell resistance to doxorubicin.
Conclusions:
- DEPTOR is a direct downstream target of the tumor suppressor p53.
- The p53-DEPTOR pathway plays a critical role in inhibiting cell proliferation and survival.
- DEPTOR contributes to p53-mediated regulation of cancer cell chemosensitivity.
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