HIF2α Acts as an mTORC1 Activator through the Amino Acid Carrier SLC7A5

被引：182

作者：

Elorza, Ainara ^{[1
]}

Soro-Arnaiz, Ines ^{[1
]}

Melendez-Rodriguez, Florinda ^{[1
]}

Rodriguez-Vaello, Victoria ^{[1
]}

Marsboom, Glenn ^{[1
]}

de Carcer, Guillermo ^{[3
,4
]}

Acosta-Iborra, Barbara ^{[1
]}

Albacete-Albacete, Lucas ^{[1
]}

Ordonez, Angel ^{[1
]}

Serrano-Oviedo, Leticia ^{[6
]}

Miguel Gimenez-Bachs, Jose ^{[7
]}

Vara-Vega, Alicia ^{[2
]}

Salinas, Antonio ^{[7
]}

Sanchez-Prieto, Ricardo ^{[6
]}

Martin del Rio, Rafael ^{[5
]}

Sanchez-Madrid, Francisco ^{[2
]}

Malumbres, Marcos ^{[3
,4
]}

Landazuri, Manuel O. ^{[1
]}

Aragones, Julian ^{[1
]}

机构：

[1] Autonomous Univ Madrid, Res Inst Princesa, Hosp Univ Santa Cristina, Res Unit, Madrid 28009, Spain

[2] Autonomous Univ Madrid, Res Inst Princesa, Hosp Univ La Princesa, Immunol Dept, Madrid 28006, Spain

[3] Spanish Natl Canc Res Ctr CNIO, Cell Div, E-28029 Madrid, Spain

[4] Spanish Natl Canc Res Ctr CNIO, Canc Grp, E-28029 Madrid, Spain

[5] Hosp Univ Ramon y Cajal, Dept Invest, Madrid 28034, Spain

[6] UCLM, Ctr Reg Invest Biomed, Lab Oncol Mol, Albacete 02008, Spain

[7] UCLM, Fac Med, Complejo Hosp Univ Albacete, Serv Urol, Albacete 02006, Spain

来源：

MOLECULAR CELL | 2012年 / 48卷 / 05期

关键词：

CELL-CYCLE ARREST; HIF-ALPHA; PROLYL HYDROXYLATION; TUMOR SUPPRESSION; IN-VIVO; HYPOXIA; GROWTH; PROLIFERATION; HIF-1-ALPHA; COMPLEX;

D O I：

10.1016/j.molcel.2012.09.017

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

The mammalian target of rapamycin (mTOR) pathway, which is essential for cell proliferation, is repressed in certain cell types in hypoxia. However, hypoxia-inducible factor 2 alpha (HIF2 alpha) can act as a proliferation-promoting factor in some biological settings. This paradoxical situation led us to study whether HIF2 alpha has a specific effect on mTORC1 regulation. Here we show that activation of the HIF2 alpha pathway increases mTORC1 activity by upregulating expression of the amino acid carrier SLC7A5. At the molecular level we also show that HIF2 alpha binds to the Slc7a5 proximal promoter. Our findings identify a link between the oxygen-sensing HIF2 alpha pathway and mTORC1 regulation, revealing the molecular basis of the tumor-promoting properties of HIF2 alpha in von Hippel-Lindau-deficient cells. We also describe relevant physiological scenarios, including those that occur in liver and lung tissue, wherein HIF2 alpha or low-oxygen tension drive mTORC1 activity and SLC7A5 expression.

引用

页码：681 / 691

页数：11

共 40 条

[1]

Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex [J].