TEAD1 (TEA Domain Transcription Factor 1) Promotes Smooth Muscle Cell Proliferation Through Upregulating SLC1A5 (Solute Carrier Family 1 Member 5)-Mediated Glutamine Uptake

Islam Osman, Xiangqin He, Jinhua Liu, Kunzhe Dong, Tong Wen, Fanzhi Zhang, Luyi Yu, Guoqing Hu, Hongbo Xin, Wei Zhang, Jiliang Zhou

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Rationale: TEAD (TEA domain transcription factor) 1- A major effector of the Hippo signaling pathway- A cts as an oncoprotein in a variety of tumors. However, the function of TEAD1 in vascular smooth muscle cells (VSMCs) remains unclear. Objective: To assess the role of TEAD1 in vascular injury-induced smooth muscle proliferation and delineate the mechanisms underlying its action. Methods and Results: We found that TEAD1 expression is enhanced in mouse femoral artery after wire injury and correlates with the activation of mTORC1 (mechanistic target of rapamycin complex 1) signaling in vivo. Using an inducible smooth muscle-specific Tead1 KO (knockout) mouse model, we found that specific deletion of Tead1 in adult VSMCs is sufficient to attenuate arterial injury-induced neointima formation due to inhibition of mTORC1 activation and VSMC proliferation. Furthermore, we found that TEAD1 plays a unique role in VSMCs, where it not only downregulates VSMC differentiation markers but also activates mTORC1 signaling, leading to enhanced VSMC proliferation. Using whole-transcriptome sequencing analysis, we identified Slc1a5 (solute carrier family 1 member 5)- A key glutamine transporter- A s a novel TEAD1 target gene. SLC1A5 overexpression mimicked TEAD1 in promoting mTORC1 activation and VSMC proliferation. Moreover, depletion of SLC1A5 by silencing RNA or blocking SLC1A5-mediated glutamine uptake attenuated TEAD1-dependent mTORC1 activation and VSMC proliferation. Conclusions: Our study unravels a novel mechanism by which TEAD1 promotes VSMC proliferation via transcriptional induction of SLC1A5, thereby activating mTORC1 signaling and promoting neointima formation.

Original languageEnglish (US)
Pages (from-to)1309-1322
Number of pages14
JournalCirculation research
Volume124
Issue number9
DOIs
StatePublished - Apr 26 2019

Fingerprint

Glutamine
Vascular Smooth Muscle
Smooth Muscle Myocytes
Transcription Factors
Cell Proliferation
Neointima
Smooth Muscle
Vascular System Injuries
Oncogene Proteins
Differentiation Antigens
Wounds and Injuries
Gene Expression Profiling
Femoral Artery
RNA Interference
Knockout Mice
mechanistic target of rapamycin complex 1
Cell Differentiation
Down-Regulation
Genes

Keywords

  • animals
  • downregulation
  • glutamine
  • mice
  • myocytes, smooth muscle
  • neoplasms
  • transcription factors

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

TEAD1 (TEA Domain Transcription Factor 1) Promotes Smooth Muscle Cell Proliferation Through Upregulating SLC1A5 (Solute Carrier Family 1 Member 5)-Mediated Glutamine Uptake. / Osman, Islam; He, Xiangqin; Liu, Jinhua; Dong, Kunzhe; Wen, Tong; Zhang, Fanzhi; Yu, Luyi; Hu, Guoqing; Xin, Hongbo; Zhang, Wei; Zhou, Jiliang.

In: Circulation research, Vol. 124, No. 9, 26.04.2019, p. 1309-1322.

Research output: Contribution to journalArticle

Osman, Islam ; He, Xiangqin ; Liu, Jinhua ; Dong, Kunzhe ; Wen, Tong ; Zhang, Fanzhi ; Yu, Luyi ; Hu, Guoqing ; Xin, Hongbo ; Zhang, Wei ; Zhou, Jiliang. / TEAD1 (TEA Domain Transcription Factor 1) Promotes Smooth Muscle Cell Proliferation Through Upregulating SLC1A5 (Solute Carrier Family 1 Member 5)-Mediated Glutamine Uptake. In: Circulation research. 2019 ; Vol. 124, No. 9. pp. 1309-1322.
@article{2e62ab85fec547858d8155a55a984c67,
title = "TEAD1 (TEA Domain Transcription Factor 1) Promotes Smooth Muscle Cell Proliferation Through Upregulating SLC1A5 (Solute Carrier Family 1 Member 5)-Mediated Glutamine Uptake",
abstract = "Rationale: TEAD (TEA domain transcription factor) 1- A major effector of the Hippo signaling pathway- A cts as an oncoprotein in a variety of tumors. However, the function of TEAD1 in vascular smooth muscle cells (VSMCs) remains unclear. Objective: To assess the role of TEAD1 in vascular injury-induced smooth muscle proliferation and delineate the mechanisms underlying its action. Methods and Results: We found that TEAD1 expression is enhanced in mouse femoral artery after wire injury and correlates with the activation of mTORC1 (mechanistic target of rapamycin complex 1) signaling in vivo. Using an inducible smooth muscle-specific Tead1 KO (knockout) mouse model, we found that specific deletion of Tead1 in adult VSMCs is sufficient to attenuate arterial injury-induced neointima formation due to inhibition of mTORC1 activation and VSMC proliferation. Furthermore, we found that TEAD1 plays a unique role in VSMCs, where it not only downregulates VSMC differentiation markers but also activates mTORC1 signaling, leading to enhanced VSMC proliferation. Using whole-transcriptome sequencing analysis, we identified Slc1a5 (solute carrier family 1 member 5)- A key glutamine transporter- A s a novel TEAD1 target gene. SLC1A5 overexpression mimicked TEAD1 in promoting mTORC1 activation and VSMC proliferation. Moreover, depletion of SLC1A5 by silencing RNA or blocking SLC1A5-mediated glutamine uptake attenuated TEAD1-dependent mTORC1 activation and VSMC proliferation. Conclusions: Our study unravels a novel mechanism by which TEAD1 promotes VSMC proliferation via transcriptional induction of SLC1A5, thereby activating mTORC1 signaling and promoting neointima formation.",
keywords = "animals, downregulation, glutamine, mice, myocytes, smooth muscle, neoplasms, transcription factors",
author = "Islam Osman and Xiangqin He and Jinhua Liu and Kunzhe Dong and Tong Wen and Fanzhi Zhang and Luyi Yu and Guoqing Hu and Hongbo Xin and Wei Zhang and Jiliang Zhou",
year = "2019",
month = "4",
day = "26",
doi = "10.1161/CIRCRESAHA.118.314187",
language = "English (US)",
volume = "124",
pages = "1309--1322",
journal = "Circulation Research",
issn = "0009-7330",
publisher = "Lippincott Williams and Wilkins",
number = "9",

}

TY - JOUR

T1 - TEAD1 (TEA Domain Transcription Factor 1) Promotes Smooth Muscle Cell Proliferation Through Upregulating SLC1A5 (Solute Carrier Family 1 Member 5)-Mediated Glutamine Uptake

AU - Osman, Islam

AU - He, Xiangqin

AU - Liu, Jinhua

AU - Dong, Kunzhe

AU - Wen, Tong

AU - Zhang, Fanzhi

AU - Yu, Luyi

AU - Hu, Guoqing

AU - Xin, Hongbo

AU - Zhang, Wei

AU - Zhou, Jiliang

PY - 2019/4/26

Y1 - 2019/4/26

N2 - Rationale: TEAD (TEA domain transcription factor) 1- A major effector of the Hippo signaling pathway- A cts as an oncoprotein in a variety of tumors. However, the function of TEAD1 in vascular smooth muscle cells (VSMCs) remains unclear. Objective: To assess the role of TEAD1 in vascular injury-induced smooth muscle proliferation and delineate the mechanisms underlying its action. Methods and Results: We found that TEAD1 expression is enhanced in mouse femoral artery after wire injury and correlates with the activation of mTORC1 (mechanistic target of rapamycin complex 1) signaling in vivo. Using an inducible smooth muscle-specific Tead1 KO (knockout) mouse model, we found that specific deletion of Tead1 in adult VSMCs is sufficient to attenuate arterial injury-induced neointima formation due to inhibition of mTORC1 activation and VSMC proliferation. Furthermore, we found that TEAD1 plays a unique role in VSMCs, where it not only downregulates VSMC differentiation markers but also activates mTORC1 signaling, leading to enhanced VSMC proliferation. Using whole-transcriptome sequencing analysis, we identified Slc1a5 (solute carrier family 1 member 5)- A key glutamine transporter- A s a novel TEAD1 target gene. SLC1A5 overexpression mimicked TEAD1 in promoting mTORC1 activation and VSMC proliferation. Moreover, depletion of SLC1A5 by silencing RNA or blocking SLC1A5-mediated glutamine uptake attenuated TEAD1-dependent mTORC1 activation and VSMC proliferation. Conclusions: Our study unravels a novel mechanism by which TEAD1 promotes VSMC proliferation via transcriptional induction of SLC1A5, thereby activating mTORC1 signaling and promoting neointima formation.

AB - Rationale: TEAD (TEA domain transcription factor) 1- A major effector of the Hippo signaling pathway- A cts as an oncoprotein in a variety of tumors. However, the function of TEAD1 in vascular smooth muscle cells (VSMCs) remains unclear. Objective: To assess the role of TEAD1 in vascular injury-induced smooth muscle proliferation and delineate the mechanisms underlying its action. Methods and Results: We found that TEAD1 expression is enhanced in mouse femoral artery after wire injury and correlates with the activation of mTORC1 (mechanistic target of rapamycin complex 1) signaling in vivo. Using an inducible smooth muscle-specific Tead1 KO (knockout) mouse model, we found that specific deletion of Tead1 in adult VSMCs is sufficient to attenuate arterial injury-induced neointima formation due to inhibition of mTORC1 activation and VSMC proliferation. Furthermore, we found that TEAD1 plays a unique role in VSMCs, where it not only downregulates VSMC differentiation markers but also activates mTORC1 signaling, leading to enhanced VSMC proliferation. Using whole-transcriptome sequencing analysis, we identified Slc1a5 (solute carrier family 1 member 5)- A key glutamine transporter- A s a novel TEAD1 target gene. SLC1A5 overexpression mimicked TEAD1 in promoting mTORC1 activation and VSMC proliferation. Moreover, depletion of SLC1A5 by silencing RNA or blocking SLC1A5-mediated glutamine uptake attenuated TEAD1-dependent mTORC1 activation and VSMC proliferation. Conclusions: Our study unravels a novel mechanism by which TEAD1 promotes VSMC proliferation via transcriptional induction of SLC1A5, thereby activating mTORC1 signaling and promoting neointima formation.

KW - animals

KW - downregulation

KW - glutamine

KW - mice

KW - myocytes, smooth muscle

KW - neoplasms

KW - transcription factors

UR - http://www.scopus.com/inward/record.url?scp=85064906005&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85064906005&partnerID=8YFLogxK

U2 - 10.1161/CIRCRESAHA.118.314187

DO - 10.1161/CIRCRESAHA.118.314187

M3 - Article

C2 - 30801233

AN - SCOPUS:85064906005

VL - 124

SP - 1309

EP - 1322

JO - Circulation Research

JF - Circulation Research

SN - 0009-7330

IS - 9

ER -