title: Map2k4 functions as a tumor suppressor in lung adenocarcinoma and inhibits tumor cell invasion by decreasing peroxisome proliferator-activated receptor γ2 expression.
abstract: MAP2K4 encodes a dual-specificity kinase (mitogen-activated protein kinase kinase 4, or MKK4) that is mutated in a variety of human malignancies, but the biochemical properties of the mutant kinases and their roles in tumorigenesis have not been fully elucidated. Here we showed that 8 out of 11 cancer-associated MAP2K4 mutations reduce MKK4 protein stability or impair its kinase activity. On the basis of findings from bioinformatic studies on human cancer cell lines with homozygous MAP2K4 loss, we posited that MKK4 functions as a tumor suppressor in lung adenocarcinomas that develop in mice owing to expression of mutant Kras and Tp53. Conditional Map2k4 inactivation in the bronchial epithelium of mice had no discernible effect alone but increased the multiplicity and accelerated the growth of incipient lung neoplasias induced by oncogenic Kras. MKK4 suppressed the invasion and metastasis of Kras-Tp53-mutant lung adenocarcinoma cells. MKK4 deficiency increased peroxisomal proliferator-activated receptor γ2 (PPARγ2) expression through noncanonical MKK4 substrates, and PPARγ2 enhanced tumor cell invasion. We conclude that Map2k4 functions as a tumor suppressor in lung adenocarcinoma and inhibits tumor cell invasion by decreasing PPARγ2 levels.
authors: Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors: Young-Ho
authors: YH
authors: Ahn
authors: Yanan
authors: Y
authors: Yang
authors: Don L
authors: DL
authors: Gibbons
authors: Chad J
authors: CJ
authors: Creighton
authors: Fei
authors: F
authors: Yang
authors: Ignacio I
authors: II
authors: Wistuba
authors: Wei
authors: W
authors: Lin
authors: Nishan
authors: N
authors: Thilaganathan
authors: Cristina A
authors: CA
authors: Alvarez
authors: Jonathon
authors: J
authors: Roybal
authors: Elizabeth J
authors: EJ
authors: Goldsmith
authors: Cathy
authors: C
authors: Tournier
authors: Jonathan M
authors: JM
authors: Kurie
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers / Q000235:genetics; D004795:Enzyme Stability; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048670:MAP Kinase Kinase 4 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D047495:PPAR gamma / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D017931:DNA Primers; D050505:Mutant Proteins; D047495:PPAR gamma; D025521:Tumor Suppressor Proteins; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human