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.
Dipartimento di Genetica, Biologia e Biochimica, Università di Torino, 10126 Torino, Italy.
Roberta
R
Ferretti
Valeria
V
Palumbo
Augusta
A
Di Savino
Silvia
S
Velasco
Mauro
M
Sbroggiò
Paolo
P
Sportoletti
Lucia
L
Micale
Emilia
E
Turco
Lorenzo
L
Silengo
Gioacchino
G
Palumbo
Emilio
E
Hirsch
Julie
J
Teruya-Feldstein
Silvia
S
Bonaccorsi
Pier Paolo
PP
Pandolfi
Maurizio
M
Gatti
Guido
G
Tarone
Mara
M
Brancaccio
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