title: Role of Gadd45a in Wip1-dependent regulation of intestinal tumorigenesis.
abstract: Conversion of intestinal stem cells into tumor-initiating cells is an early step in Apc(Min)-induced polyposis. Wild-type p53-induced phosphatase 1 (Wip1)-dependent activation of a DNA damage response and p53 has a permanent role in suppression of stem cell conversion, and deletion of Wip1 lowers the tumor burden in Apc(Min) mice. Here we show that cyclin-dependent kinase inhibitor 2a, checkpoint kinase 2, and growth arrest and DNA damage gene 45a (Gadd45a) exert critical functions in the tumor-resistant phenotype of Wip1-deficient mice. We further identified Gadd45a as a haploinsufficient gene in the regulation of Wip1-dependent tumor resistance in mice. Gadd45a appears to function through its ability to activate the Jnk-dependent signaling pathway that in turn is a necessary mediator of the proapoptotic functions of p53 that respond to activation of the β-catenin signaling pathway. We propose that silencing of Gadd45a is sufficient to override p53 activation in the presence of active β-catenin under conditions of an enhanced DNA damage response.
authors.affiliation: Institute of Molecular and Cell Biology, Cell Cycle Control and Tumorigenesis Group, Singapore 138673, Singapore.
authors.forename: O N
authors.initials: ON
authors.lastname: Demidov
authors.forename: Y
authors.initials: Y
authors.lastname: Zhu
authors.forename: C
authors.initials: C
authors.lastname: Kek
authors.forename: A R
authors.initials: AR
authors.lastname: Goloudina
authors.forename: N
authors.initials: N
authors.lastname: Motoyama
authors.forename: D V
authors.initials: DV
authors.lastname: Bulavin
mesh_terms: D000818:Animals; D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic; D064447:Checkpoint Kinase 2; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004260:DNA Repair; D017491:Genes, APC; D044483:Intestinal Polyposis / Q000378:metabolism / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000071636:Protein Phosphatase 2C; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism; D000097642:GADD45 Proteins
chemical_list: D018797:Cell Cycle Proteins; D064447:Checkpoint Kinase 2; D019941:Cyclin-Dependent Kinase Inhibitor p16; D048031:JNK Mitogen-Activated Protein Kinases; D009687:Nuclear Proteins; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C; D017346:Protein Serine-Threonine Kinases; D043562:Receptors, G-Protein-Coupled; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; C417743:Cdkn2a protein, mouse; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins; C493597:Lgr5 protein, mouse; C578633:Chek2 protein, mouse; C000607468:Ppm1d protein, mouse