title: 14-3-3γ Prevents Centrosome Amplification and Neoplastic Progression.
abstract: More than 80% of malignant tumors show centrosome amplification and clustering. Centrosome amplification results from aberrations in the centrosome duplication cycle, which is strictly coordinated with DNA-replication-cycle. However, the relationship between cell-cycle regulators and centrosome duplicating factors is not well understood. This report demonstrates that 14-3-3γ localizes to the centrosome and 14-3-3γ loss leads to centrosome amplification. Loss of 14-3-3γ results in the phosphorylation of NPM1 at Thr-199, causing early centriole disjunction and centrosome hyper-duplication. The centrosome amplification led to aneuploidy and increased tumor formation in mice. Importantly, an increase in passage of the 14-3-3γ-knockdown cells led to an increase in the number of cells containing clustered centrosomes leading to the generation of pseudo-bipolar spindles. The increase in pseudo-bipolar spindles was reversed and an increase in the number of multi-polar spindles was observed upon expression of a constitutively active 14-3-3-binding-defective-mutant of cdc25C (S216A) in the 14-3-3γ knockdown cells. The increase in multi-polar spindle formation was associated with decreased cell viability and a decrease in tumor growth. Our findings uncover the molecular basis of regulation of centrosome duplication by 14-3-3γ and inhibition of tumor growth by premature activation of the mitotic program and the disruption of centrosome clustering.
authors.affiliation: Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Center, Mumbai 410210, India.
authors.forename: Amitabha
authors.initials: A
authors.lastname: Mukhopadhyay
authors.affiliation: Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Center, Mumbai 410210, India.
authors.forename: Lalit
authors.initials: L
authors.lastname: Sehgal
authors.affiliation: Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Center, Mumbai 410210, India.
authors.forename: Arunabha
authors.initials: A
authors.lastname: Bose
authors.affiliation: Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Center, Mumbai 410210, India.
authors.forename: Anushree
authors.initials: A
authors.lastname: Gulvady
authors.affiliation: Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore 560064, India.
authors.forename: Parijat
authors.initials: P
authors.lastname: Senapati
authors.affiliation: Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Center, Mumbai 410210, India.
authors.forename: Rahul
authors.initials: R
authors.lastname: Thorat
authors.affiliation: Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Center, Mumbai 410210, India.
authors.forename: Srikanta
authors.initials: S
authors.lastname: Basu
authors.affiliation: Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Center, Mumbai 410210, India.
authors.forename: Khyati
authors.initials: K
authors.lastname: Bhatt
authors.affiliation: Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Center, Mumbai 410210, India.
authors.forename: Amol S
authors.initials: AS
authors.lastname: Hosing
authors.affiliation: National Institute of Immunology, New Delhi 110067, India.
authors.forename: Renu
authors.initials: R
authors.lastname: Balyan
authors.affiliation: Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai 400005, India.
authors.forename: Lalit
authors.initials: L
authors.lastname: Borde
authors.affiliation: Transcription and Disease Laboratory, Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore 560064, India.
authors.forename: Tapas K
authors.initials: TK
authors.lastname: Kundu
authors.affiliation: Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Center, Mumbai 410210, India.
authors.forename: Sorab N
authors.initials: SN
authors.lastname: Dalal
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism*; D000782:Aneuploidy; D000818:Animals; D002453:Cell Cycle; D045744:Cell Line, Tumor; D018385:Centrosome / Q000378:metabolism* / Q000473:pathology; D043171:Chromosomal Instability; D017353:Gene Deletion; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism; D000090243:Nucleophosmin; D010766:Phosphorylation; D013912:Threonine / Q000737:chemistry; D020687:cdc25 Phosphatases / Q000378:metabolism
chemical_list: D048948:14-3-3 Proteins; C000716967:NPM1 protein, human; C000715570:Npm1 protein, mouse; D009687:Nuclear Proteins; D000090243:Nucleophosmin; D013912:Threonine; C517010:Cdc25c protein, mouse; D020687:cdc25 Phosphatases