title: Mammalian Ste20-like kinase 4 promotes pituitary cell proliferation and survival under hypoxia.
abstract: The genetic and molecular mechanisms that initiate and maintain pituitary tumorigenesis are poorly understood. Nonfunctioning tumors of the gonadotrope lineage represent 35% of all tumors; are usually macroadenomas, often resulting in hypopituitarism; and have no medical treatments. Using expression microarrays combined with whole-genome copy number screens on individual human tumors, we identified the mammalian sterile-20-like kinase (MST4) transcript, which was amplified within chromosome Xq26.2 in one tumor and up-regulated in all gonadotrope tumor samples. MST4 mRNA and protein were consistently overexpressed in human tumors compared with normal pituitaries. To mimic the pituitary tumor microenvironment, a hypoxia model using LβT2 murine gonadotrope cells was created to examine the functional role of the kinase. During long-term hypoxia, MST4 expression increased colony formation in a soft agar assay and rates of cell proliferation by activating p38 MAPK and AKT. Under short-term severe hypoxic stress, MST4 decreased the rates of apoptosis via p38 MAPK, AKT, hypoxia-inducible factor-1, and its cell-specific downstream targets. Analysis of MST4 mutants confirmed the importance of the kinase sequence but not the regulatory C terminus for its functional effects. Together these data identify the MST4 kinase as a novel candidate to mediate human pituitary tumorigenesis in a hypoxic environment and position it as a potential therapeutic target.
authors: Departments of Medicine (W.X., A.J.K., M.X., K.K.-V., S.P.C., M.E.W.), Anesthesiology (K.S.B.), Pathology (B.K.K.-D.), and Neurosurgery (K.O.L.), University of Colorado School of Medicine, Aurora, Colorado 80045; and Research Service (K.K.-V., M.E.W.), Veterans Affairs Medical Center, Denver, Colorado 80220.
authors: Weipeng
authors: W
authors: Xiong
authors: Aaron J
authors: AJ
authors: Knox
authors: Mei
authors: M
authors: Xu
authors: Katja
authors: K
authors: Kiseljak-Vassiliades
authors: Sean P
authors: SP
authors: Colgan
authors: Kelley S
authors: KS
authors: Brodsky
authors: Bette K
authors: BK
authors: Kleinschmidt-Demasters
authors: Kevin O
authors: KO
authors: Lillehei
authors: Margaret E
authors: ME
authors: Wierman
mesh_terms: D017209:Apoptosis; D015687:Cell Hypoxia; D049109:Cell Proliferation; D002470:Cell Survival; D019610:Cytoprotection; D056915:DNA Copy Number Variations / Q000235:genetics; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D052681:Gonadotrophs / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D050505:Mutant Proteins / Q000737:chemistry / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010902:Pituitary Gland / Q000201:enzymology* / Q000473:pathology*; D010911:Pituitary Neoplasms / Q000235:genetics / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological; D014410:Tumor Stem Cell Assay; D015854:Up-Regulation / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099317:Hippo Kinases
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D050505:Mutant Proteins; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; C497442:HIF1A protein, human; C430908:STK26 protein, human; D000099317:Hippo Kinases
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