Estrogen-Related Hormones Induce Apoptosis by Stabilizing Schlafen-12 Protein Turnover

Mol Cell. 2019 Sep 19;75(6):1103-1116.e9. doi: 10.1016/j.molcel.2019.06.040.

Dianrong Li ¹, Jie Chen ², Youwei Ai ¹, Xiaoqiong Gu ³, Li Li ⁴, Di Che ⁵, Zhaodi Jiang ¹, Lin Li ¹, She Chen ¹, Huangwei Huang ¹, Jiawen Wang ¹, Tao Cai ¹, Yang Cao ¹, Xiangbin Qi ¹, Xiaodong Wang ⁶

Affiliations

1 National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China.
2 College of Biological Sciences, China Agricultural University, Beijing 100083, China; National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China.
3 Department of Blood Transfusion, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China; Clinical Biological Resource Bank and Clinical Lab, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China.
4 Department of Gynecology and Obstetrics, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China.
5 Clinical Biological Resource Bank and Clinical Lab, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China.
6 National Institute of Biological Sciences, 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China; Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China. Electronic address: wangxiaodong@nibs.ac.cn.

PMID: 31420216 DOI: 10.1016/j.molcel.2019.06.040

Abstract

The mitochondrial pathway of Apoptosis is controlled by the ratio of anti- and pro-apoptotic members of the Bcl-2 Family of proteins. The molecular events underlying how a given physiological stimulus changes this ratio to trigger Apoptosis remains unclear. We report here that human 17-β-estradiol (E2) and its related steroid Hormones induce Apoptosis by binding directly to phosphodiesterase 3A, which in turn recruits and stabilizes an otherwise fast-turnover protein Schlafen 12 (SLFN12). The elevated SLFN12 binds to ribosomes to exclude the recruitment of signal recognition particles (SRPs), thereby blocking the continuous protein translation occurring on the endoplasmic reticulum of E2-treated cells. These proteins include Bcl-2 and Mcl-1, whose ensuing decrease triggers Apoptosis. The SLFN12 protein and an Apoptosis activation marker were co-localized in syncytiotrophoblast of human placentas, where levels of estrogen-related Hormones are high, and dynamic cell turnover by Apoptosis is critical for successful implantation and placenta development.

Keywords

PDE3A; SLFN12; apoptosis; estrogen.

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