Fam72a functions as a cell-cycle-controlled gene during proliferation and antagonizes apoptosis through reprogramming PP2A substrates

Yuan Fu; Xiaofan Jia; Jinwei Yuan; Yuting Yang; Teng Zhang; Qiujing Yu; Jun Zhou; Ting Wang

doi:10.1016/j.devcel.2023.02.006

Fam72a functions as a cell-cycle-controlled gene during proliferation and antagonizes apoptosis through reprogramming PP2A substrates

Dev Cell. 2023 Mar 13;58(5):398-415.e7. doi: 10.1016/j.devcel.2023.02.006. Epub 2023 Mar 2.

Authors

Yuan Fu¹, Xiaofan Jia², Jinwei Yuan², Yuting Yang², Teng Zhang², Qiujing Yu³, Jun Zhou⁴, Ting Wang⁵

Affiliations

¹ Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China; Department of Thoracic Oncology, Tianjin Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Lung Cancer Center, Tianjin Medical University, Tianjin 300070, China. Electronic address: fuyuan@tmu.edu.cn.
² Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
³ Department of Immunology and Key Laboratory of Immune Microenvironment and Disease, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
⁴ Department of Genetics and Cell Biology, State Key Laboratory of Medicinal Chemical Biology, Haihe Laboratory of Cell Ecosystem, College of Life Sciences, Nankai University, Tianjin 300071, China.
⁵ Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China; Department of Thoracic Oncology, Tianjin Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Lung Cancer Center, Tianjin Medical University, Tianjin 300070, China. Electronic address: twang1@tmu.edu.cn.

PMID: 36868233
DOI: 10.1016/j.devcel.2023.02.006

Abstract

The cell cycle is key to life. After decades of research, it is unclear whether any parts of this process have yet to be identified. Fam72a is a poorly characterized gene and is evolutionarily conserved across multicellular organisms. Here, we have found that Fam72a is a cell-cycle-regulated gene that is transcriptionally and post-transcriptionally regulated by FoxM1 and APC/C, respectively. Functionally, Fam72a directly binds to tubulin and both the Aα and B56 subunits of PP2A-B56 to modulate tubulin and Mcl1 phosphorylation, which in turn affects the progression of the cell cycle and signaling of apoptosis. Moreover, Fam72a is involved in early responses to chemotherapy, and it efficiently antagonizes various anticancer compounds such as CDK and Bcl2 inhibitors. Thus, Fam72a switches the tumor-suppressive PP2A to be oncogenic by reprogramming its substrates. These findings identify a regulatory axis of PP2A and a protein member in the cell cycle and tumorigenesis regulatory network in human cells.

Keywords: Fam72a; Mcl1; PP2A; apoptosis; cell proliferation.

Publication types

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

MeSH terms

Apoptosis / genetics
Cell Proliferation / genetics
Humans
Phosphorylation
Protein Phosphatase 2* / genetics
Protein Phosphatase 2* / metabolism
Tubulin* / metabolism

Substances

Protein Phosphatase 2
Tubulin
FAM72A protein, human