Post-GWAS functional analysis identifies CUX1 as a regulator of p16INK4a and cellular senescence

被引：13

作者：

Jiang, Danli ^{[1
]}

Sun, Wei ^{[2
,3
]}

Wu, Ting ^{[1
,4
]}

Zou, Meijuan ^{[1
,5
]}

Vasamsetti, Sathish Babu ^{[2
,3
]}

Zhang, Xiaoyu ^{[1
]}

Zhao, Yihan ^{[1
]}

Phillippi, Julie A. ^{[6
]}

Sawalha, Amr H. ^{[7
,8
,9
]}

Tavakoli, Sina ^{[10
,11
]}

Dutta, Partha ^{[2
,3
]}

Florentin, Jonathan ^{[2
,3
,12
]}

Chan, Stephen Y. ^{[2
,3
]}

Tollison, Tammy S. ^{[13
]}

Wu, Di ^{[14
,15
]}

Cui, Jing ^{[16
]}

Huntress, Ian ^{[13
,17
]}

Peng, Xinxia ^{[13
,18
]}

Finkel, Toren ^{[1
,12
]}

Li, Gang ^{[1
,12
]}

机构：

[1] Univ Pittsburgh, Aging Inst, Pittsburgh, PA 15260 USA

[2] Univ Pittsburgh, Sch Med, Ctr Pulm Vasc Biol & Med, Pittsburgh Heart Lung Blood & Vasc Med Inst, Pittsburgh, PA USA

[3] Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA

[4] Cent South Univ, Xiangya Sch Med, Dept Med, Changsha, Peoples R China

[5] Nanjing Med Univ, Dept Pharmacol, Nanjing, Peoples R China

[6] Univ Pittsburgh, Dept Cardiothorac Surg, Sch Med, Pittsburgh, PA USA

[7] Univ Pittsburgh, Sch Med, Dept Pediat Med, Pittsburgh, PA USA

[8] Univ Pittsburgh, Sch Med, Dept Immunol, Pittsburgh, PA USA

[9] Univ Pittsburgh, Sch Med, Lupus Ctr Excellence, Pittsburgh, PA USA

[10] Univ Pittsburgh, UPMC Presbyterian Hosp, Dept Radiol, Pittsburgh, PA USA

[11] Univ Pittsburgh, UPMC Presbyterian Hosp, Dept Med, Pittsburgh, PA USA

[12] Univ Pittsburgh, Dept Med, Div Cardiol, Med Ctr, Pittsburgh, PA 15213 USA

[13] North Carolina State Univ, Dept Mol Biomed Sci, Coll Vet Med, Raleigh, NC USA

[14] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27515 USA

[15] Univ N Carolina, Div Oral & Craniofacial Hlth Sci, Adam Sch Dent, Chapel Hill, NC 27515 USA

[16] Brigham & Womens Hosp, Dept Med, Div Rheumatol Inflammat & Immun, 75 Francis St, Boston, MA 02115 USA

[17] North Carolina State Univ, Bioinformat Grad Program, Raleigh, NC USA

[18] North Carolina State Univ, Bioinformat Res Ctr, Raleigh, NC USA

来源：

NATURE AGING | 2022年 / 2卷 / 02期

关键词：

PREMATURE SENESCENCE; TELOMERASE ACTIVITY; TUMOR-SUPPRESSOR; CDKN2A/B LOCUS; DNA-REPAIR; CELLS; EXPRESSION; P53; FIBROBLASTS; HALLMARKS;

D O I：

10.1038/s43587-022-00177-0

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Accumulation of senescent cells with age is an important driver of aging and age-related diseases. However, the mechanisms and signaling pathways that regulate senescence remain elusive. In this report, we performed post-genome-wide association studies (GWAS) functional studies on the CDKN2A/B locus, a locus known to be associated with multiple age-related diseases and overall human lifespan. We demonstrate that transcription factor CUX1 (Cut-Like Homeobox1) specifically binds to an atherosclerosis-associated functional single-nucleotide polymorphism (fSNP) (rs1537371) within the locus and regulates the CDKN2A/B-encoded proteins p14(ARF), p15(INK4b) and p16(INK4a) and the antisense noncoding RNA in the CDK4 (INK4) locus (ANRIL) in endothelial cells (ECs). Endothelial CUX1 expression correlates with telomeric length and is induced by both DNA-damaging agents and oxidative stress. Moreover, induction of CUX1 expression triggers both replicative and stress-induced senescence via activation of p16(INK4a) expression. Thus, our studies identify CUX1 as a regulator of p16(INK4a)-dependent endothelial senescence and a potential therapeutic target for atherosclerosis and other age-related diseases.

引用

页码：140 / +

页数：28

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