The RNA binding protein RALY suppresses p53 activity and promotes lung tumorigenesis

Hao Hu; Kailiang Zhao; Debao Fang; Zhongyu Wang; Ning Yu; Bo Yao; Kaiyue Liu; Fang Wang; Yide Mei

doi:10.1016/j.celrep.2023.112288

The RNA binding protein RALY suppresses p53 activity and promotes lung tumorigenesis

Cell Rep. 2023 Apr 25;42(4):112288. doi: 10.1016/j.celrep.2023.112288. Epub 2023 Mar 22.

Authors

Hao Hu¹, Kailiang Zhao¹, Debao Fang¹, Zhongyu Wang¹, Ning Yu¹, Bo Yao¹, Kaiyue Liu¹, Fang Wang¹, Yide Mei²

Affiliations

¹ Hefei National Laboratory for Physical Sciences at Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, Anhui, China.
² Hefei National Laboratory for Physical Sciences at Microscale, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, Anhui, China; The CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, Anhui, China; Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230027, Anhui, China. Electronic address: meiyide@ustc.edu.cn.

PMID: 36952348
DOI: 10.1016/j.celrep.2023.112288

Abstract

The tumor suppressor p53 plays a pivotal role in tumor prevention. The activity of p53 is mainly restrained by the ubiquitin E3 ligase Mdm2. However, it is not well understood how the Mdm2-p53 pathway is intricately regulated. Here we report that the RNA binding protein RALY functions as an oncogenic factor in lung cancer. RALY simultaneously binds to Mdm2 and the deubiquitinating enzyme USP7. Via these interactions, RALY not only stabilizes Mdm2 by stimulating the deubiquitinating activity of USP7 toward Mdm2 but also increases the trans-E3 ligase activity of Mdm2 toward p53. Consequently, RALY enhances Mdm2-mediated ubiquitination and degradation of p53. Functionally, RALY promotes lung tumorigenesis, at least partially, via negative regulation of p53. These findings suggest that RALY destabilizes p53 by modulating the function of Mdm2 at multiple levels. Our study also indicates a critical role for RALY in promoting lung tumorigenesis via p53 inhibition.

Keywords: CP: Cancer; CP: Molecular biology; Mdm2; RALY; USP7; p53; tumorigenesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Transformation, Neoplastic / genetics
Heterogeneous-Nuclear Ribonucleoprotein Group C / genetics
Heterogeneous-Nuclear Ribonucleoprotein Group C / metabolism
Humans
Lung / metabolism
Protein Binding
Proto-Oncogene Proteins c-mdm2* / metabolism
RNA-Binding Proteins / metabolism
Tumor Suppressor Protein p53* / metabolism
Ubiquitin-Protein Ligases / metabolism
Ubiquitin-Specific Peptidase 7 / metabolism
Ubiquitination

Substances

Heterogeneous-Nuclear Ribonucleoprotein Group C
Proto-Oncogene Proteins c-mdm2
RALY protein, human
RNA-Binding Proteins
Tumor Suppressor Protein p53
Ubiquitin-Protein Ligases
Ubiquitin-Specific Peptidase 7
USP7 protein, human
TP53 protein, human