PERK Is a Haploinsufficient Tumor Suppressor: Gene Dose Determines Tumor-Suppressive Versus Tumor Promoting Properties of PERK in Melanoma
| Autor: | Gao Zhang, Ireneusz Majsterek, Maria Cristina Garcia Paredes, Serge Y. Fuchs, Dariusz Pytel, Yuliya V. Katlinskaya, Kirk A. Staschke, Lawrence Wu, Katarzyna Mackiewicz, Meenhard Herlyn, Olga S. Chajewski, Yan Gao, Akihiro Yoshida, J. Alan Diehl, Shuo Qie |
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| Rok vydání: | 2016 |
| Předmět: |
Melanomas
0301 basic medicine Cancer Research Cell cycle checkpoint Cancer Treatment Gene Dosage Apoptosis Haploinsufficiency Endoplasmic Reticulum Epithelium eIF-2 Kinase Cell Signaling Animal Cells Medicine and Health Sciences PERK inhibitors Cell Cycle and Cell Division Melanoma Genetics (clinical) Cultured Tumor Cells Cell Death 3. Good health Cell Transformation Neoplastic Oncology Cell Processes Melanocytes Melanoma Cells Biological Cultures Cellular Types Anatomy Research Article Signal Transduction Proto-Oncogene Proteins B-raf endocrine system Cell signaling lcsh:QH426-470 Tumor suppressor gene Biology Research and Analysis Methods Small Molecule Libraries 03 medical and health sciences Cyclins Cell Line Tumor Genetics medicine Humans Chromatophores Protein kinase A Immunohistochemistry Techniques Molecular Biology Ecology Evolution Behavior and Systematics Tumor Suppressor Proteins Cancers and Neoplasms Biology and Life Sciences Epithelial Cells Cell Biology Cell Cycle Checkpoints Cell Cultures medicine.disease Histochemistry and Cytochemistry Techniques lcsh:Genetics Biological Tissue 030104 developmental biology Tumor progression Mutation Immunology Immunologic Techniques Unfolded Protein Response Unfolded protein response Cancer research |
| Zdroj: | PLoS Genetics, Vol 12, Iss 12, p e1006518 (2016) PLoS Genetics |
| ISSN: | 1553-7404 |
| DOI: | 10.1371/journal.pgen.1006518 |
| Popis: | 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 UPR-dependent 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 BrafV600E-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 BrafV600E-dependent tumors highlighting the clinical value of targeting PERK. Author Summary PERK is critical for progression of specific cancers and has provided stimulus for the generation of small molecule PERK inhibitors. Paradoxically, the anti-proliferative and pro-death functions of PERK have potential tumor suppressive qualities. We demonstrate that PERK can function as either a tumor suppressor or a pro-adaptive tumor promoter and the nature of its function is determined by gene dose. Preclinical studies suggest a therapeutic threshold exists for PERK inhibitors. |
| Databáze: | OpenAIRE |
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