PERK Is a Haploinsufficient Tumor Suppressor: Gene Dose Determines Tumor-Suppressive Versus Tumor Promoting Properties of PERK in Melanoma

被引：45

作者：

Pytel, Dariusz ^{[1
]}

Gao, Yan ^{[1
]}

Mackiewicz, Katarzyna ^{[1
]}

Katlinskaya, Yuliya V. ^{[2
]}

Staschke, Kirk A. ^{[3
]}

Paredes, Maria C. G. ^{[3
]}

Yoshida, Akihiro ^{[1
]}

Qie, Shuo ^{[1
]}

Zhang, Gao ^{[4
]}

Chajewski, Olga S. ^{[5
]}

Wu, Lawrence ^{[4
]}

Majsterek, Ireneusz ^{[6
]}

Herlyn, Meenhard ^{[4
]}

Fuchs, Serge Y. ^{[2
]}

Diehl, J. Alan ^{[1
]}

机构：

[1] Med Univ South Carolina, Hollings Canc Ctr, Dept Biochem & Mol Biol, Charleston, SC 29425 USA

[2] Univ Penn, Sch Vet Med, Dept Biomed Sci, Philadelphia, PA 19104 USA

[3] Eli Lilly & Co, Lilly Res Labs, Oncol Discovery Res, Lilly Corp Ctr Dc1104, Indianapolis, IN 46285 USA

[4] Wistar Inst Anat & Biol, Mol & Cellular Oncogenesis Program, 3601 Spruce St, Philadelphia, PA 19104 USA

[5] Med Univ South Carolina, Dept Pathol & Lab Med, Charleston, SC USA

[6] Med Univ Lodz, Dept Clin Chem & Biochem, Lodz, Poland

来源：

PLOS GENETICS | 2016年 / 12卷 / 12期

基金：

美国国家卫生研究院;

关键词：

UNFOLDED PROTEIN RESPONSE; ENDOPLASMIC-RETICULUM STRESS; TRANSCRIPTION FACTOR ATF6; ER STRESS; DEPENDENT REGULATION; METASTATIC MELANOMA; ADIPOCYTE DIFFERENTIATION; TRANSLATIONAL CONTROL; MAMMALIAN-CELLS; HYPOXIC STRESS;

D O I：

10.1371/journal.pgen.1006518

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学];

摘要：

The unfolded protein response (UPR) regulates cell fate following exposure of cells to endoplasmic reticulum stresses. PERK, a UPR protein kinase, regulates protein synthesis and while linked with cell survival, exhibits activities associated with both tumor progression and tumor suppression. For example, while cells lacking PERK are sensitive to UPRdependent cell death, acute activation of PERK triggers both apoptosis and cell cycle arrest, which would be expected to contribute tumor suppressive activity. We have evaluated these activities in the BRAF-dependent melanoma and provide evidence revealing a complex role for PERK in melanoma where a 50% reduction is permissive for Braf(V600E)-dependent transformation, while complete inhibition is tumor suppressive. Consistently, PERK mutants identified in human melanoma are hypomorphic with dominant inhibitory function. Strikingly, we demonstrate that small molecule PERK inhibitors exhibit single agent efficacy against Braf(V600E)-dependent tumors highlighting the clinical value of targeting PERK.

引用

页数：22

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