title: AMP-Activated Protein Kinase Directly Phosphorylates and Destabilizes Hedgehog Pathway Transcription Factor GLI1 in Medulloblastoma.
abstract: The Hedgehog (Hh) pathway regulates cell differentiation and proliferation during development by controlling the Gli transcription factors. Cell fate decisions and progression toward organ and tissue maturity must be coordinated, and how an energy sensor regulates the Hh pathway is not clear. AMP-activated protein kinase (AMPK) is an important sensor of energy stores and controls protein synthesis and other energy-intensive processes. AMPK is directly responsive to intracellular AMP levels, inhibiting a wide range of cell activities if ATP is low and AMP is high. Thus, AMPK can affect development by influencing protein synthesis and other processes needed for growth and differentiation. Activation of AMPK reduces GLI1 protein levels and stability, thus blocking Sonic-hedgehog-induced transcriptional activity. AMPK phosphorylates GLI1 at serines 102 and 408 and threonine 1074. Mutation of these three sites into alanine prevents phosphorylation by AMPK. This leads to increased GLI1 protein stability, transcriptional activity, and oncogenic potency.
authors.affiliation: Department of Basic Medical Sciences, Purdue University College of Veterinary Medicine, West Lafayette, IN 47907, USA.
authors.forename: Yen-Hsing
authors.initials: YH
authors.lastname: Li
authors.affiliation: Departments of Developmental Biology, Genetics, and Bioengineering, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Basic Medical Sciences, Purdue University College of Veterinary Medicine, West Lafayette, IN 47907, USA.
authors.forename: Yung-Yi C
authors.initials: YY
authors.lastname: Mosley
authors.affiliation: Bindley Bioscience Center, Purdue University, West Lafayette, IN 47906, USA.
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Hedrick
authors.affiliation: Bindley Bioscience Center, Purdue University, West Lafayette, IN 47906, USA.
authors.forename: Lake N
authors.initials: LN
authors.lastname: Paul
authors.affiliation: Departments of Developmental Biology, Genetics, and Bioengineering, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Chang
authors.affiliation: Center for Cancer Research, Purdue University College of Veterinary Medicine, West Lafayette, IN 47907, USA; Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, West Lafayette, IN 47907, USA.
authors.forename: GuangJun
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Biological Science and Technology, National Chiao Tung University, Hsin-Chu 300, Taiwan.
authors.forename: Yu-Kuo
authors.initials: YK
authors.lastname: Wang
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Max R
authors.initials: MR
authors.lastname: Banko
authors.affiliation: Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Brunet
authors.affiliation: Center for Cancer Research, Purdue University College of Veterinary Medicine, West Lafayette, IN 47907, USA; Department of Animal Sciences, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Shihuan
authors.initials: S
authors.lastname: Kuang
authors.affiliation: Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115 Taiwan.
authors.forename: Jen-Leih
authors.initials: JL
authors.lastname: Wu
authors.affiliation: Department of Basic Medical Sciences, Purdue University College of Veterinary Medicine, West Lafayette, IN 47907, USA; Center for Cancer Research, Purdue University College of Veterinary Medicine, West Lafayette, IN 47907, USA.
authors.forename: Chun-Ju
authors.initials: CJ
authors.lastname: Chang
authors.affiliation: Departments of Developmental Biology, Genetics, and Bioengineering, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Scott
authors.affiliation: Department of Basic Medical Sciences, Purdue University College of Veterinary Medicine, West Lafayette, IN 47907, USA; Center for Cancer Research, Purdue University College of Veterinary Medicine, West Lafayette, IN 47907, USA. Electronic address: jyyang@purdue.edu.
authors.forename: Jer-Yen
authors.initials: JY
authors.lastname: Yang
mesh_terms: D016475:3T3 Cells; D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D057809:HEK293 Cells; D006801:Humans; D008527:Medulloblastoma / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism*; D015027:Zebrafish; D000071676:Zinc Finger Protein GLI1
chemical_list: C400551:GLI1 protein, human; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D055372:AMP-Activated Protein Kinases