PMID- 25164809 OWN - NLM STAT- MEDLINE DCOM- 20150212 LR - 20220331 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 289 IP - 43 DP - 2014 Oct 24 TI - PDK4 protein promotes tumorigenesis through activation of cAMP-response element-binding protein (CREB)-Ras homolog enriched in brain (RHEB)-mTORC1 signaling cascade. PG - 29739-49 LID - 10.1074/jbc.M114.584821 [doi] AB - Mechanistic target of rapamycin (mTOR) integrates multiple extracellular and intracellular signals to regulate cell growth and survival. Hyperactivation of mTOR has been observed in various cancers. Regulation of mTOR activity is thus of importance in physiological processes and tumor development. Here, we present pyruvate dehydrogenase kinase 4 (PDK4) as a novel regulator of mTORC1 signaling. mTORC1 activity was augmented with PDK4 overexpression and reduced by PDK4 suppression in various cell lines. Furthermore, PDK4 bound to cAMP-response element-binding protein (CREB) and prevented its degradation. The enhanced CREB consequently transactivated the expression of Ras homolog enriched in brain (RHEB), a direct key activator of mTORC1, independent of AMP-activated protein kinase or tuberous sclerosis complex protein 2. PDK4 potentiated the mTORC1 effectors hypoxia-inducible factor 1alpha and pyruvate kinase isozymes M2 and promoted aerobic glycolysis (Warburg effect). Knockdown of PDK4 suppressed the tumor development of cancer cells with activated mTORC1. The abundance of PDK4 dictated the responsiveness of cells to the mTOR inhibitor, rapamycin. Combinatory suppression of mTOR and PDK4 exerted synergistic inhibition on cancer cell proliferation. Therefore, PDK4 promotes tumorigenesis through activation of the CREB-RHEB-mTORC1 signaling cascade. CI - (c) 2014 by The American Society for Biochemistry and Molecular Biology, Inc. FAU - Liu, Zhibo AU - Liu Z AD - From the State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Beijing 100005, China and. FAU - Chen, Xinxin AU - Chen X AD - From the State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Beijing 100005, China and. FAU - Wang, Ying AU - Wang Y AD - From the State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Beijing 100005, China and the Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, China. FAU - Peng, Haiyong AU - Peng H AD - From the State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Beijing 100005, China and. FAU - Wang, Yanan AU - Wang Y AD - From the State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Beijing 100005, China and. FAU - Jing, Yanling AU - Jing Y AD - From the State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Beijing 100005, China and. FAU - Zhang, Hongbing AU - Zhang H AD - From the State Key Laboratory of Medical Molecular Biology, Department of Physiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Graduate School of Peking Union Medical College, Beijing 100005, China and hbzhang@ibms.pumc.edu.cn hbzhang2006@gmail.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140827 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (Cyclic AMP Response Element-Binding Protein) RN - 0 (Hypoxia-Inducible Factor 1, alpha Subunit) RN - 0 (Isoenzymes) RN - 0 (Multiprotein Complexes) RN - 0 (Neuropeptides) RN - 0 (Ras Homolog Enriched in Brain Protein) RN - 0 (Rheb protein, mouse) RN - 0 (Tuberous Sclerosis Complex 2 Protein) RN - 0 (Tumor Suppressor Proteins) RN - 9LSH52S3LQ (Dichloroacetic Acid) RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.1.- (pyruvate dehydrogenase kinase 4) RN - EC 2.7.1.40 (Pyruvate Kinase) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - EC 3.1.3.67 (PTEN Phosphohydrolase) RN - EC 3.6.5.2 (Monomeric GTP-Binding Proteins) SB - IM MH - AMP-Activated Protein Kinases/metabolism MH - Aerobiosis/drug effects MH - Animals MH - Carcinogenesis/metabolism/*pathology MH - Cell Line, Tumor MH - Cell Proliferation/drug effects MH - Cyclic AMP Response Element-Binding Protein/*metabolism MH - Dichloroacetic Acid/pharmacology MH - Glycolysis/drug effects MH - HEK293 Cells MH - Humans MH - Hypoxia-Inducible Factor 1, alpha Subunit/metabolism MH - Isoenzymes/metabolism MH - Mechanistic Target of Rapamycin Complex 1 MH - Mice MH - Mice, Nude MH - Monomeric GTP-Binding Proteins/*metabolism MH - Multiprotein Complexes/antagonists & inhibitors/metabolism MH - Neuropeptides/*metabolism MH - PTEN Phosphohydrolase/metabolism MH - Protein Kinases/*metabolism MH - Proto-Oncogene Proteins c-akt/metabolism MH - Pyruvate Kinase/metabolism MH - Ras Homolog Enriched in Brain Protein MH - *Signal Transduction/drug effects MH - TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism MH - Transcription, Genetic/drug effects MH - Tuberous Sclerosis Complex 2 Protein MH - Tumor Suppressor Proteins/metabolism MH - Up-Regulation/drug effects PMC - PMC4207987 OTO - NOTNLM OT - Cellular Regulation OT - DNA-Protein Interaction OT - Mechanistic Target of Rapamycin (mTOR) OT - Pyruvate Dehydrogenase Kinase 4 OT - Ras Homolog Enriched in Brain OT - Signaling OT - Tumorigenesis OT - Warburg Effect OT - cAMP-response Element-binding Protein (CREB) EDAT- 2014/08/29 06:00 MHDA- 2015/02/13 06:00 PMCR- 2015/10/24 CRDT- 2014/08/29 06:00 PHST- 2014/08/29 06:00 [entrez] PHST- 2014/08/29 06:00 [pubmed] PHST- 2015/02/13 06:00 [medline] PHST- 2015/10/24 00:00 [pmc-release] AID - S0021-9258(20)37312-9 [pii] AID - M114.584821 [pii] AID - 10.1074/jbc.M114.584821 [doi] PST - ppublish SO - J Biol Chem. 2014 Oct 24;289(43):29739-49. doi: 10.1074/jbc.M114.584821. Epub 2014 Aug 27.