Id1 Overexpression Induces Tetraploidization and Multiple Abnormal Mitotic Phenotypes by Modulating Aurora A

Abstract

The basic helix-loop-helix transcription factor, Id1, was shown to induce tetraploidy in telomerase-immortalized nasopharyngeal epithelial cells in this study. Using both transient and stable Id1-expressing cell models, multiple mitotic aberrations were detected, including centrosome amplification, binucleation, spindle defects, and microtubule perturbation. Many of these abnormal phenotypes have previously been reported in cells overexpressing Aurora A. Further experiments showed that Id1 could stabilize Aurora A, whereas knocking down Aurora A expression in Id1-expressing cells could rescue some of the mitotic defects. The mechanisms by which Aurora A could be modulated by Id1 were explored. DNA amplification of the Aurora A locus was not involved. Id1 could only weakly activate the transcriptional activity of the Aurora A promoter. We found that Id1 overexpression could affect Aurora A degradation, leading to its stabilization. Aurora A is normally degraded from mitosis exit by the APC/C Cdh1 -mediated proteasomal proteolysis pathway. Our results revealed that Id1 and Cdh1 are binding partners. The association of Id1 and Cdh1 was found to be dependent on the canonical destruction box motif of Id1, the increased binding of which may compete with the interaction between Cdh1 and Aurora A, leading to stabilization of Aurora A in Id1-overexpressing cells.

Niche-Based Screening in Multiple Myeloma Identifies a Kinesin-5 Inhibitor with Improved Selectivity over Hematopoietic Progenitors

“…The top 10 compounds that downregulate ID1 included the anti-mitotic paclitaxel (Figure S4B). This finding, in addition to literature reports of ID1 expression being associated with abnormal mitoses(Man et al, 2008), suggested possible anti-mitotic effects of BRD9876. Cell-cycle analysis of MM1S treated with 10 μM BRD9876 revealed rapid arrest of cells at the G2/M phase starting as early as 2h of treatment (Figure 3B).…”

A novel role for the deubiquitinase USP1 in the control of centrosome duplication

“…Interestingly, ID1, but not ID2 and ID3, is localized at centrosome and ID1 overexpression results in accumulation of supernumerary centrosomes. [37][38][39] Our findings suggest the possibility for the involvement of ID1 in USP1-induced centrosome amplification. Indeed, an increase in Id1 abundance was detected in wt-Usp1 NIH3T3 cells (Fig.…”

“…22 Interestingly, ID1, but not other ID proteins (ID2, ID3 and ID4), is localized at centrosome and forced expression of ID1 results in accumulation of supernumerary centrosomes, [37][38][39] suggesting that stabilization of ID1 through USP1 overexpression can induce centrosome amplification. To explore this possibility, we generated NIH3T3 cells stably transduced with Id1 and compared the induction of centrosome amplification with wt-Usp1 NIH3T3 cells (Fig.…”

Illicit survival of cancer cells during polyploidization and depolyploidization

“…59 Overexpression of the potential oncogene ID1, a dominant negative inhibitor of basic helix-loop-helix transcription factors, induces supernumerary centrosomes and centrioles, cytokinesis failure and tetraploidization. 60 Thus, tetraploidy can follow the inactivation of oncosuppressor proteins or the activation of oncoproteins.…”