PMID- 37357506
OWN - NLM
STAT- MEDLINE
DCOM- 20230818
LR  - 20230818
IS  - 1097-4652 (Electronic)
IS  - 0021-9541 (Linking)
VI  - 238
IP  - 8
DP  - 2023 Aug
TI  - PRPF8 controls alternative splicing of PIRH2 to modulate the p53 pathway and 
      survival of human ESCs.
PG  - 1909-1920
LID - 10.1002/jcp.31066 [doi]
AB  - Human embryonic stem cells (hESCs) have great potential for developmental biology 
      and regenerative medicine. However, extensive apoptosis often occurs when hESCs 
      respond to various stresses or injuries. Understanding the molecular control and 
      identifying new factors associated with hESC survival are fundamental to ensure 
      the high quality of hESCs. In this study, we report that PRPF8, an RNA 
      spliceosome component, is essential for hESC survival. PRPF8 knockdown (KD) 
      induces p53 protein accumulation and activates the p53 pathway, leading to 
      apoptosis in hESCs. Strikingly, silencing of p53 rescues PRPF8 KD-induced 
      apoptosis, indicating that PRPF8 KD triggers hESC apoptosis through activating 
      the p53 pathway. In search for the mechanism by which p53 pathway is activated by 
      PRPF8 KD, we find that PRPF8 KD alters alternative splicing of many genes, 
      including PIRH2 which encodes an E3 ubiquitin ligase of p53. PIRH2 has several 
      isoforms such as PIRH2A, PIRH2B, and PIRH2C. Intriguingly, PRPF8 KD specifically 
      increases the transcript level of the PIRH2B isoform, which lacks a RING domain 
      and E3 ligase activity. Functionally, PIRH2B KD partially rescues the reduction 
      in cell numbers and upregulation of P21 caused by PRPF8 KD in hESCs. The finding 
      suggests that PRPF8 controls alternative splicing of PIRH2 to maintain the 
      balance of p53 pathway activity and survival of hESCs. The PRPF8/PIRH2/p53 axis 
      identified here provides new insights into how p53 pathway and hESC survival are 
      precisely regulated at multiple layers, highlighting an important role of 
      posttranscriptional machinery in supporting hESC survival.
CI  - (c) 2023 Wiley Periodicals LLC.
FAU - Sun, Yiyang
AU  - Sun Y
AD  - CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for 
      Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, 
      Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 
      China.
FAU - Zhang, Lingling
AU  - Zhang L
AD  - CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for 
      Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, 
      Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 
      China.
AD  - Shanghai Key Laboratory of Reproductive Medicine, Department of Histoembryology, 
      Genetics and Developmental Biology, Shanghai JiaoTong University School of 
      Medicine, Shanghai, China.
FAU - Fang, Zhuoqing
AU  - Fang Z
AD  - CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for 
      Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, 
      Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 
      China.
FAU - Liu, Dingyu
AU  - Liu D
AD  - Shanghai Key Laboratory of Reproductive Medicine, Department of Histoembryology, 
      Genetics and Developmental Biology, Shanghai JiaoTong University School of 
      Medicine, Shanghai, China.
FAU - Shao, Min
AU  - Shao M
AD  - CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for 
      Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, 
      Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 
      China.
FAU - Liu, Yujie
AU  - Liu Y
AD  - Shanghai Key Laboratory of Reproductive Medicine, Department of Histoembryology, 
      Genetics and Developmental Biology, Shanghai JiaoTong University School of 
      Medicine, Shanghai, China.
FAU - Liao, Bing
AU  - Liao B
AD  - Shanghai Key Laboratory of Reproductive Medicine, Department of Histoembryology, 
      Genetics and Developmental Biology, Shanghai JiaoTong University School of 
      Medicine, Shanghai, China.
FAU - Jin, Ying
AU  - Jin Y
AUID- ORCID: 0000-0003-0070-2048
AD  - CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for 
      Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, 
      Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai, 
      China.
AD  - Shanghai Key Laboratory of Reproductive Medicine, Department of Histoembryology, 
      Genetics and Developmental Biology, Shanghai JiaoTong University School of 
      Medicine, Shanghai, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230625
PL  - United States
TA  - J Cell Physiol
JT  - Journal of cellular physiology
JID - 0050222
RN  - 0 (Protein Isoforms)
RN  - 0 (PRPF8 protein, human)
RN  - 0 (RNA-Binding Proteins)
RN  - 0 (Tumor Suppressor Protein p53)
RN  - EC 2.3.2.27 (Ubiquitin-Protein Ligases)
RN  - EC 2.3.2.27 (RCHY1 protein, human)
SB  - IM
MH  - Humans
MH  - *Alternative Splicing/genetics
MH  - Protein Isoforms/genetics/metabolism
MH  - RNA-Binding Proteins/genetics/metabolism
MH  - *Tumor Suppressor Protein p53/genetics/metabolism
MH  - Ubiquitin-Protein Ligases/genetics/metabolism
MH  - Ubiquitination
OTO - NOTNLM
OT  - PRPF8
OT  - RNA alternative splicing
OT  - p53 signaling pathway
OT  - survival and death of hESCs
EDAT- 2023/06/26 06:41
MHDA- 2023/08/17 06:43
CRDT- 2023/06/26 02:22
PHST- 2023/05/05 00:00 [revised]
PHST- 2022/10/05 00:00 [received]
PHST- 2023/05/13 00:00 [accepted]
PHST- 2023/08/17 06:43 [medline]
PHST- 2023/06/26 06:41 [pubmed]
PHST- 2023/06/26 02:22 [entrez]
AID - 10.1002/jcp.31066 [doi]
PST - ppublish
SO  - J Cell Physiol. 2023 Aug;238(8):1909-1920. doi: 10.1002/jcp.31066. Epub 2023 Jun 
      25.