Morgana/chp-1, a ROCK inhibitor involved in centrosome duplication and tumorigenesis

Roberta Ferretti; Valeria Palumbo; Augusta Di Savino; Silvia Velasco; Mauro Sbroggiò; Paolo Sportoletti; Lucia Micale; Emilia Turco; Lorenzo Silengo; Gioacchino Palumbo; Emilio Hirsch; Julie Teruya-Feldstein; Silvia Bonaccorsi; Pier Paolo Pandolfi; Maurizio Gatti; Guido Tarone; Mara Brancaccio

doi:10.1016/j.devcel.2009.12.020

Morgana/chp-1, a ROCK inhibitor involved in centrosome duplication and tumorigenesis

Dev Cell. 2010 Mar 16;18(3):486-95. doi: 10.1016/j.devcel.2009.12.020.

Authors

Roberta Ferretti¹, Valeria Palumbo, Augusta Di Savino, Silvia Velasco, Mauro Sbroggiò, Paolo Sportoletti, Lucia Micale, Emilia Turco, Lorenzo Silengo, Gioacchino Palumbo, Emilio Hirsch, Julie Teruya-Feldstein, Silvia Bonaccorsi, Pier Paolo Pandolfi, Maurizio Gatti, Guido Tarone, Mara Brancaccio

Affiliation

¹ Dipartimento di Genetica, Biologia e Biochimica, Università di Torino, 10126 Torino, Italy.

PMID: 20230755
DOI: 10.1016/j.devcel.2009.12.020

Abstract

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Breast Neoplasms / genetics
Carrier Proteins / genetics
Carrier Proteins / metabolism*
Cell Transformation, Neoplastic
Centrosome / metabolism*
Centrosome / pathology*
Down-Regulation
Drosophila Proteins / genetics
Drosophila Proteins / metabolism
Embryonic Development / genetics
Embryonic Development / physiology
Enzyme Inhibitors / metabolism
Female
Fungal Proteins / genetics
HSP90 Heat-Shock Proteins / metabolism
Humans
Mice
Mice, Knockout
Mitosis / genetics
Mitosis / physiology
Molecular Chaperones / genetics
Molecular Chaperones / metabolism
Mutation
Neoplasms, Experimental / etiology
Nuclear Proteins / metabolism
Nucleophosmin
Pregnancy
rho-Associated Kinases / antagonists & inhibitors*

Substances

CHORD protein, Drosophila
Carrier Proteins
Chp-1 protein, mouse
Drosophila Proteins
Enzyme Inhibitors
Fungal Proteins
HSP90 Heat-Shock Proteins
Molecular Chaperones
NPM1 protein, human
Nuclear Proteins
Nucleophosmin
LZ-8 protein, Ganoderma lucidum
rho-Associated Kinases