Morgana/chp-1, a ROCK inhibitor involved in centrosome duplication and tumorigenesis.
Centrosome abnormalities lead to genomic instability and are a common feature of many cancer cells. Here we show that mutations in morgana/chp-1 result in centrosome amplification and lethality in both Drosophila and mouse, and that the fly centrosome phenotype is fully rescued by the human ortholog of morgana. In mouse cells, morgana forms a complex with Hsp90 and ROCK I and II, and directly binds ROCK II. Morgana downregulation promotes the interaction between ROCK II and nucleophosmin (NPM), leading to an increased ROCK II kinase activity, which results in centrosome amplification. Morgana(+/-) primary cells and mice display an increased susceptibility to neoplastic transformation. In addition, tumor tissue array histochemical analysis revealed that morgana is underexpressed in a large fraction of breast and lung human cancers. Thus, morgana/chp-1 appears to prevent both centrosome amplification and tumorigenesis.
Ferretti
Roberta
R
Dipartimento di Genetica, Biologia e Biochimica, Università di Torino, 10126 Torino, Italy.
Palumbo
Valeria
V
Di Savino
Augusta
A
Velasco
Silvia
S
Sbroggiò
Mauro
M
Sportoletti
Paolo
P
Micale
Lucia
L
Turco
Emilia
E
Silengo
Lorenzo
L
Palumbo
Gioacchino
G
Hirsch
Emilio
E
Teruya-Feldstein
Julie
J
Bonaccorsi
Silvia
S
Pandolfi
Pier Paolo
PP
Gatti
Maurizio
M
Tarone
Guido
G
Brancaccio
Mara
M
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic; D018385:Centrosome / Q000378:metabolism* / Q000473:pathology*; D015536:Down-Regulation; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D047108:Embryonic Development / Q000235:genetics / Q000502:physiology; D004791:Enzyme Inhibitors / Q000378:metabolism; D005260:Female; D005656:Fungal Proteins / Q000235:genetics; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis / Q000235:genetics / Q000502:physiology; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009374:Neoplasms, Experimental / Q000209:etiology; D009687:Nuclear Proteins / Q000378:metabolism; D000090243:Nucleophosmin; D011247:Pregnancy; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
C000602135:CHORD protein, Drosophila; D002352:Carrier Proteins; C478383:Chp-1 protein, mouse; D029721:Drosophila Proteins; D004791:Enzyme Inhibitors; D005656:Fungal Proteins; D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D000090243:Nucleophosmin; C061148:LZ-8 protein, Ganoderma lucidum; D054460:rho-Associated Kinases