title: Morgana acts as a proto-oncogene through inhibition of a ROCK-PTEN pathway.
abstract: Morgana/CHP-1 is a ubiquitously expressed protein able to inhibit ROCK II kinase activity. We have previously demonstrated that morgana haploinsufficiency leads to multiple centrosomes, genomic instability, and higher susceptibility to tumour development. While a large fraction of human cancers has shown morgana down-regulation, a small subset of tumours was shown to express high morgana levels. Here we demonstrate that high morgana expression in different breast cancer subtypes correlates with high tumour grade, mitosis number, and lymph node positivity. Moreover, morgana overexpression induces transformation in NIH-3T3 cells and strongly protects them from various apoptotic stimuli. From a mechanistic point of view, we demonstrate that morgana causes PTEN destabilization, by inhibiting ROCK activity, hence triggering the PI3K/AKT survival pathway. In turn, morgana down-regulation in breast cancer cells that express high morgana levels increases PTEN expression and leads to sensitization of cells to chemotherapy.
authors.affiliation: Department of Biotechnology and Health Sciences, University of Torino, Torino, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Fusella
authors.forename: Roberta
authors.initials: R
authors.lastname: Ferretti
authors.forename: Daniele
authors.initials: D
authors.lastname: Recupero
authors.forename: Stefania
authors.initials: S
authors.lastname: Rocca
authors.forename: Augusta
authors.initials: A
authors.lastname: Di Savino
authors.forename: Giusy
authors.initials: G
authors.lastname: Tornillo
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Silengo
authors.forename: Emilia
authors.initials: E
authors.lastname: Turco
authors.forename: Sara
authors.initials: S
authors.lastname: Cabodi
authors.forename: Paolo
authors.initials: P
authors.lastname: Provero
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Pandolfi
authors.forename: Anna
authors.initials: A
authors.lastname: Sapino
authors.forename: Guido
authors.initials: G
authors.lastname: Tarone
authors.forename: Mara
authors.initials: M
authors.lastname: Brancaccio
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D018385:Centrosome / Q000473:pathology; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D006801:Humans; D051379:Mice; D018832:Molecular Chaperones; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D018832:Molecular Chaperones; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000090063:Proto-Oncogene Mas; D051057:Proto-Oncogene Proteins c-akt; D054460:rho-Associated Kinases; C469743:CHP1 protein, human; C478383:Chp-1 protein, mouse; C000715470:MAS1 protein, human; C494929:PTEN protein, human; C487757:Pten protein, mouse
keywords: PTEN; ROCK; breast cancer; chemoresistance; morgana