HSF4 promotes G1/S arrest in human lens epithelial cells by stabilizing p53.
The differentiation from constantly dividing epithelial cells into secondary fiber cells is a key step during lens development. Failure in this process, which requires cell proliferation inhibition and cell cycle exit, causes cataract formation. HSF4 (Heat Shock Transcription Factor 4) gene mutations may lead to both congenital and senile cataract. However, how HSF4 mutations induce cataract formation remains obscure. In this study, we demonstrate that HSF4 can suppress the proliferation of human lens epithelial cells (HLECs) by promoting G1/S arrest in a p53-dependent manner. In contrast, HSF4 with cataract causative mutations fail to cause cell cycle arrest and have no obvious effect on cell proliferation. We further identify that HSF4 recruits p53 in the nucleus and promotes its transcriptional activity, leading to the expression of its target gene p21 in HLECs. HSF4, but not its cataract-causing mutants, stabilizes p53 protein and inhibits its ubiquitin degradation. Our data reveal that HSF4 may work as a switch between lens epithelial cell proliferation and secondary fiber cell differentiation, a process which mainly depends on p53. Through demonstration of this novel downstream pathway of HSF4, our results help uncover the pathogenic mechanisms caused by HSF4 mutations.
Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China.
Mi
M
Huang
Key Laboratory of Kidney Disease Pathogenesis and Intervention of Hubei Province, Key Discipline of Pharmacy of Hubei Department of Education, Medical College, Hubei Polytechnic University, Huangshi, Hubei, PR China.
Duanzhuo
D
Li
Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China.
Yuwen
Y
Huang
Key Laboratory of Molecular and Cellular Immunology, Department of Cell Biology and Genetics, Henan University School of Medicine, Kaifeng, Henan, PR China.
Xiukun
X
Cui
Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China.
Shengjie
S
Liao
Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China.
Jiuxiang
J
Wang
Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China.
Fei
F
Liu
Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China.
Chang
C
Li
Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China.
Meng
M
Gao
Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China.
Jiaxiang
J
Chen
Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China.
Zhaohui
Z
Tang
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China; Truhlsen Eye Institute, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA. Electronic address: dwli1688@hotmail.com.
David Wan-Cheng
DW
Li
Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China. Electronic address: lium@mail.hust.edu.cn.
Mugen
M
Liu
D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics*; D005812:Genes, Switch; D000076249:Heat Shock Transcription Factors; D006801:Humans; D007908:Lens, Crystalline / Q000166:cytology / Q000502:physiology; D050505:Mutant Proteins / Q000378:metabolism; D011485:Protein Binding; D055550:Protein Stability; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation / Q000235:genetics; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D004268:DNA-Binding Proteins; C102948:HSF4 protein, human; D000076249:Heat Shock Transcription Factors; D050505:Mutant Proteins; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53
Cataract; Cell cycle arrest; HSF4; Proliferation; p53 stability