TP53 promotes lineage commitment of human embryonic stem cells through ciliogenesis and sonic hedgehog signaling

被引：19

作者：

Sivakumar, Sushama ^{[1
]}

Qi, Shutao ^{[2
,3
]}

Cheng, Ningyan ^{[1
]}

Sathe, Adwait A. ^{[4
]}

Kanchwala, Mohammed ^{[4
]}

Kumar, Ashwani ^{[4
]}

Evers, Bret M. ^{[5
]}

Xing, Chao ^{[4
,6
,7
]}

Yu, Hongtao ^{[1
,2
,3
]}

机构：

[1] Univ Texas Southwestern Med Ctr Dallas, Dept Pharmacol, 6001 Forest Pk Rd, Dallas, TX 75390 USA

[2] Westlake Lab Life Sci & Biomed, Hangzhou, Zhejiang, Peoples R China

[3] Westlake Univ, Sch Life Sci, Hangzhou, Zhejiang, Peoples R China

[4] Univ Texas Southwestern Med Ctr Dallas, Eugene McDermott Ctr Human Growth & Dev, Dallas, TX 75390 USA

[5] Univ Texas Southwestern Med Ctr Dallas, Dept Pathol, 5323 Harry Hines Blvd, Dallas, TX 75390 USA

[6] Univ Texas Southwestern Med Ctr Dallas, Dept Bioinformat, Dallas, TX 75390 USA

[7] Univ Texas Southwestern Med Ctr Dallas, Dept Populat & Data Sci, Dallas, TX 75390 USA

来源：

CELL REPORTS | 2022年 / 38卷 / 07期

基金：

美国国家卫生研究院;

关键词：

PRIMARY CILIA; REPRESSOR FUNCTIONS; P53; FAMILY; HUMAN ES; DIFFERENTIATION; CANCER; EXPRESSION; MUTATIONS; PHOSPHORYLATION; SUPPRESSION;

D O I：

10.1016/j.celrep.2022.110395

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Aneuploidy, defective differentiation, and inactivation of the tumor suppressor TP53 all occur frequently during tumorigenesis. Here, we probe the potential links among these cancer traits by inactivating TP53 in human embryonic stem cells (hESCs). TP53-/- hESCs exhibit increased proliferation rates, mitotic errors, and low-grade structural aneuploidy; produce poorly differentiated immature teratomas in mice; and fail to differentiate into neural progenitor cells (NPCs) in vitro. Genome-wide CRISPR screen reveals requirements of ciliogenesis and sonic hedgehog (Shh) pathways for hESC differentiation into NPCs. TP53 deletion causes abnormal ciliogenesis in neural rosettes. In addition to restraining cell proliferation through CDKN1A, TP53 activates the transcription of BBS9, which encodes a ciliogenesis regulator required for proper Shh signaling and NPC formation. This developmentally regulated transcriptional program of TP53 promotes ciliogenesis, restrains Shh signaling, and commits hESCs to neural lineages.

引用

页数：24

共 75 条

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