14-3-3γ Prevents Centrosome Amplification and Neoplastic Progression
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Updated: Mar 20, 2026
Live Cell Imaging to Assess the Dynamics of Metaphase Timing and Cell Fate Following Mitotic Spindle Perturbations
Published on: September 20, 2019
Amitabha Mukhopadhyay1, Lalit Sehgal1, Arunabha Bose1
1Advanced Centre for Treatment Research and Education in Cancer, Tata Memorial Center, Mumbai 410210, India.
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.
Insights
Loss of 14-3-3γ protein causes centrosome amplification, leading to aneuploidy and tumor formation. Restoring specific cell cycle functions inhibits tumor growth by disrupting abnormal cell division.
Area of Science:
- Cell Biology
- Molecular Biology
- Cancer Research
Background:
- Centrosome amplification is common in malignant tumors, arising from disruptions in the cell cycle and DNA replication.
- The precise interplay between cell cycle regulators and centrosome duplication factors remains unclear.
Purpose of the Study:
- To investigate the role of 14-3-3γ in regulating centrosome duplication and its impact on tumor formation.
- To elucidate the molecular mechanisms linking 14-3-3γ, cell cycle progression, and centrosome abnormalities.
Main Methods:
- Localization studies of 14-3-3γ at the centrosome.
- Analysis of centrosome amplification in 14-3-3γ-knockdown cells.
- Investigation of NPM1 phosphorylation at Thr-199.
- Assessment of aneuploidy and tumor formation in mice.
- Examination of spindle formation and cell viability upon cdc25C mutant expression.
Main Results:
- 14-3-3γ loss leads to centrosome amplification via NPM1 phosphorylation (Thr-199), causing early centriole disjunction.
- Centrosome amplification promotes aneuploidy and increased tumor formation in vivo.
- 14-3-3γ knockdown results in pseudo-bipolar spindles, which are reversed to multi-polar spindles by a cdc25C mutant (S216A).
- Increased multi-polar spindles correlate with reduced cell viability and tumor growth.
Conclusions:
- 14-3-3γ is a key regulator of centrosome duplication.
- Premature mitotic entry and disrupted centrosome clustering inhibit tumor growth.
- Targeting 14-3-3γ or related pathways offers potential therapeutic strategies for cancer.
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