MLF2 Negatively Regulates P53 and Promotes Colorectal Carcinogenesis

Overview

Journal Adv Sci (Weinh)

Specialty Biomedical Engineering

Date 2023 Jul 12

PMID 37438558

Authors

Debao Fang

Hao Hu

Kailiang Zhao

Aman Xu

Changjun Yu

Yong Zhu

Ning Yu

Bo Yao

Suyun Tang

Xianning Wu

Yide Mei

Affiliations

Soon will be listed here.

Abstract

Inactivation of the p53 pathway is linked to a variety of human cancers. As a critical component of the p53 pathway, ubiquitin-specific protease 7 (USP7) acts as a deubiquitinase for both p53 and its ubiquitin E3 ligase mouse double minute 2 homolog. Here, myeloid leukemia factor 2 (MLF2) is reported as a new negative regulator of p53. MLF2 interacts with both p53 and USP7. Via these interactions, MLF2 inhibits the binding of USP7 to p53 and antagonizes USP7-mediated deubiquitination of p53, thereby leading to p53 destabilization. Functionally, MLF2 plays an oncogenic role in colorectal cancer, at least partially, via the negative regulation of p53. Clinically, MLF2 is elevated in colorectal cancer and its high expression is associated with poor prognosis in patients with colorectal cancer. In wild-type-p53-containing colorectal cancer, MLF2 and p53 expressions are inversely correlated. These findings establish MLF2 as an important suppressor of p53 function. The study also reveals a critical role for the MLF2-p53 axis in promoting colorectal carcinogenesis.

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MLF2 Negatively Regulates P53 and Promotes Colorectal Carcinogenesis.

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References

Hassin O, Oren M . Drugging p53 in cancer: one protein, many targets. Nat Rev Drug Discov. 2022; 22(2):127-144. PMC: 9549847. DOI: 10.1038/s41573-022-00571-8. View

Hafner A, Bulyk M, Jambhekar A, Lahav G . The multiple mechanisms that regulate p53 activity and cell fate. Nat Rev Mol Cell Biol. 2019; 20(4):199-210. DOI: 10.1038/s41580-019-0110-x. View

Li M, Brooks C, Kon N, Gu W . A dynamic role of HAUSP in the p53-Mdm2 pathway. Mol Cell. 2004; 13(6):879-86. DOI: 10.1016/s1097-2765(04)00157-1. View

Prophet S, Rampello A, Niescier R, Gentile J, Mallik S, Koleske A . Atypical nuclear envelope condensates linked to neurological disorders reveal nucleoporin-directed chaperone activities. Nat Cell Biol. 2022; 24(11):1630-1641. PMC: 10041656. DOI: 10.1038/s41556-022-01001-y. View

Sheng Y, Saridakis V, Sarkari F, Duan S, Wu T, Arrowsmith C . Molecular recognition of p53 and MDM2 by USP7/HAUSP. Nat Struct Mol Biol. 2006; 13(3):285-91. DOI: 10.1038/nsmb1067. View

Leng R, Lin Y, Ma W, Wu H, Lemmers B, Chung S . Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation. Cell. 2003; 112(6):779-91. DOI: 10.1016/s0092-8674(03)00193-4. View

Pfister N, Prives C . Transcriptional Regulation by Wild-Type and Cancer-Related Mutant Forms of p53. Cold Spring Harb Perspect Med. 2016; 7(2). PMC: 5287061. DOI: 10.1101/cshperspect.a026054. View

Saridakis V, Sheng Y, Sarkari F, Holowaty M, Shire K, Nguyen T . Structure of the p53 binding domain of HAUSP/USP7 bound to Epstein-Barr nuclear antigen 1 implications for EBV-mediated immortalization. Mol Cell. 2005; 18(1):25-36. DOI: 10.1016/j.molcel.2005.02.029. View

Zhao K, Yang Y, Zhang G, Wang C, Wang D, Wu M . Regulation of the Mdm2-p53 pathway by the ubiquitin E3 ligase MARCH7. EMBO Rep. 2018; 19(2):305-319. PMC: 5797962. DOI: 10.15252/embr.201744465. View

10.

Look A, Kirstein M, Valentine M, Raimondi S, Cohen K, Carroll A . The t(3;5)(q25.1;q34) of myelodysplastic syndrome and acute myeloid leukemia produces a novel fusion gene, NPM-MLF1. Oncogene. 1996; 12(2):265-75. View

11.

Cummins J, Rago C, Kohli M, Kinzler K, Lengauer C, Vogelstein B . Tumour suppression: disruption of HAUSP gene stabilizes p53. Nature. 2004; 428(6982):1 p following 486. DOI: 10.1038/nature02501. View

12.

Kuefer M, Look A, Williams D, Valentine V, Naeve C, Behm F . cDNA cloning, tissue distribution, and chromosomal localization of myelodysplasia/myeloid leukemia factor 2 (MLF2). Genomics. 1996; 35(2):392-6. DOI: 10.1006/geno.1996.0376. View

13.

Dave B, Granados-Principal S, Zhu R, Benz S, Rabizadeh S, Soon-Shiong P . Targeting RPL39 and MLF2 reduces tumor initiation and metastasis in breast cancer by inhibiting nitric oxide synthase signaling. Proc Natl Acad Sci U S A. 2014; 111(24):8838-43. PMC: 4066479. DOI: 10.1073/pnas.1320769111. View

14.

Liu J, Zhang C, Hu W, Feng Z . Tumor suppressor p53 and its mutants in cancer metabolism. Cancer Lett. 2013; 356(2 Pt A):197-203. PMC: 4069248. DOI: 10.1016/j.canlet.2013.12.025. View

15.

Montes de Oca Luna R, Wagner D, Lozano G . Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53. Nature. 1995; 378(6553):203-6. DOI: 10.1038/378203a0. View

16.

Aylon Y, Oren M . The Paradox of p53: What, How, and Why?. Cold Spring Harb Perspect Med. 2016; 6(10). PMC: 5046691. DOI: 10.1101/cshperspect.a026328. View

17.

Everett R, Meredith M, Orr A, Cross A, Kathoria M, Parkinson J . A novel ubiquitin-specific protease is dynamically associated with the PML nuclear domain and binds to a herpesvirus regulatory protein. EMBO J. 1997; 16(7):1519-30. PMC: 1169756. DOI: 10.1093/emboj/16.7.1519. View

18.

Al-Eidan A, Wang Y, Skipp P, Ewing R . The USP7 protein interaction network and its roles in tumorigenesis. Genes Dis. 2022; 9(1):41-50. PMC: 8720671. DOI: 10.1016/j.gendis.2020.10.004. View

19.

Jones S, Roe A, Donehower L, Bradley A . Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53. Nature. 1995; 378(6553):206-8. DOI: 10.1038/378206a0. View

20.

Vousden K, Prives C . Blinded by the Light: The Growing Complexity of p53. Cell. 2009; 137(3):413-31. DOI: 10.1016/j.cell.2009.04.037. View