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Inhibition of tumor suppressor p73 by nerve growth factor receptor via chaperone-mediated autophagy.

ABSTRACT: The tumor suppressr p73 is a homolog of p53 and is capable of inducing cell cycle arrest and apoptosis. Here, we identify nerve growth factor receptor (NGFR, p75NTR, or CD271) as a novel negative p73 regulator. p73 activates NGFR transcription, which, in turn, promotes p73 degradation in a negative feedback loop. NGFR directly binds to p73 central DNA-binding domain and suppresses p73 transcriptional activity as well as p73-mediated apoptosis in cancer cells. Surprisingly, we uncover a previously unknown mechanism of NGFR-facilitated p73 degradation through the chaperone-mediated autophagy (CMA) pathway. Collectively, our studies demonstrate a new oncogenic function for NGFR in inactivating p73 activity by promoting its degradation through the CMA.

SUBMITTER: Nguyen D

PROVIDER: S-EPMC7749740 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Inhibition of tumor suppressor p73 by nerve growth factor receptor via chaperone-mediated autophagy.

Nguyen Daniel D Yang Kun K Chiao Lucia L Deng Yun Y Zhou Xiang X Zhang Zhen Z Zeng Shelya X SX Lu Hua H

Journal of molecular cell biology 20200901 9

The tumor suppressr p73 is a homolog of p53 and is capable of inducing cell cycle arrest and apoptosis. Here, we identify nerve growth factor receptor (NGFR, p75NTR, or CD271) as a novel negative p73 regulator. p73 activates NGFR transcription, which, in turn, promotes p73 degradation in a negative feedback loop. NGFR directly binds to p73 central DNA-binding domain and suppresses p73 transcriptional activity as well as p73-mediated apoptosis in cancer cells. Surprisingly, we uncover a previousl ...[more]

PMID: 32285119

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Project description:Chaperone-mediated autophagy (CMA) is a selective degradative process for cytosolic proteins that contributes to the maintenance of proteostasis. The signaling mechanisms that control CMA are not fully understood but might involve response to stress conditions including oxidative stress. Considering the role of CMA in redoxtasis and proteostasis, we sought to determine if the transcription factor NFE2L2/NRF2 (nuclear factor, erythroid derived 2, like 2) has an impact on CMA modulation. In this work, we identified and validated 2 NFE2L2 binding sequences in the LAMP2 gene and demonstrated in several human and mouse cell types that NFE2L2 deficiency and overexpression was linked to reduced and increased LAMP2A levels, respectively. Accordingly, lysosomal LAMP2A levels were drastically reduced in nfe2l2-knockout hepatocytes, which also displayed a marked decrease in CMA activity. Oxidant challenge with paraquat or hydrogen peroxide, or pharmacological activation of NFE2L2 with sulforaphane or dimethyl fumarate also increased LAMP2A levels and CMA activity. Overall, our study identifies for the first time basal and inducible regulation of LAMP2A, and consequently CMA activity, by NFE2L2.AbbreviationsACTB: actin, beta, ARE: antioxidant response element; ATG5: autophagy related 5; BACH1: BTB domain and CNC homolog 1; ChIP: chromatin immunoprecipitation; CMA: chaperone-mediated autophagy; DHE: dihydroethidium; DMF: dimethyl fumarate; ENCODE: Encyclopedia of DNA elements at the University of California, Santa Cruz; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GBA: glucosylceramidase beta; GFP: green fluorescent protein; HMOX1: heme oxygenase 1; H2O2: hydrogen peroxide; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; KEAP1: kelch like ECH associated protein 1; LAMP2A: lysosomal associated membrane protein 2A; LAMP2B: lysosomal associated membrane protein 2B; LAMP2C: lysosomal associated membrane protein 2C; LAMP1: lysosomal associated membrane protein 1; MAFF: MAF bZIP transcription factor F; MAFK: MAF bZIP transcription factor K; NFE2L2/NRF2: nuclear factor, erythroid derived 2, like 2; NQO1: NAD(P)H quinone dehydrogenase 1; PQ: paraquat; PI: protease inhibitors; qRT-PCR: quantitative real-time polymerase chain reaction; RNASE: ribonuclease A family member; SFN: sulforaphane; SQSTM1/p62: sequestosome 1; TBP: TATA-box binding protein.

Dataset Information

Inhibition of tumor suppressor p73 by nerve growth factor receptor via chaperone-mediated autophagy.

Publications

Inhibition of tumor suppressor p73 by nerve growth factor receptor via chaperone-mediated autophagy.

Similar Datasets

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