Antizyme, a mediator of ubiquitin-independent proteasomal degradation and its inhibitor localize to centrosomes and modulate centriole amplification

Abstract

The potential tumor suppressor antizyme and its endogenous inhibitor (antizyme inhibitor, AZI) have been implicated in the ubiquitin-independent proteasomal degradation of proteins involved in cell proliferation as well as in the regulation of polyamine levels. We show here that both antizyme and AZI concentrate at centrosomes and that antizyme preferentially associates with the maternal centriole. Interestingly, alterations in the levels of these proteins have opposing effects on centrosomes. Depletion of antizyme in various cell lines and primary cells leads to centrosome overduplication, whereas overexpression of antizyme reduces numerical centrosome abnormalities. Conversely, silencing of the antizyme inhibitor, AZI, results in a decrease of numerical centrosome abnormalities, whereas overexpression of AZI leads to centrosome overduplication. We further show that the numerical centrosome abnormalities are due to daughter centriole amplification. In summary, our results demonstrate that alterations in the antizyme/AZI balance cause numerical centrosomal defects and suggest a role for ubiquitin-independent proteasomal degradation in centrosome duplication.

Antizyme suppression leads to an increment of the cellular redox potential and an induction of HIF‐1α: Its involvement in resistance to γ‐radiation

“…AZ was also reported as a regulator of Smad1 when it functions as a transcriptional regulator of various BMP-responsive genes. Recently, Mangold et al reported on the function of antizyme as a centrosomal homeostasis (33). Although, in our study, we showed another aspect of antizyme, in that antizyme regulates the expression of ICDH and catalase, which is followed by a change of the ROS scavenging activity, we did not unveil whether the interacting target of antizyme for this physiological phenomenon is ODC or other factors.…”

Antizyme and antizyme inhibitor, a regulatory tango

“…In addition, the relative contribution of the antizyme-mediated perturbation of cyclin D1 and aurora-A on the process of cellular proliferation remains unclear. It was also recently demonstrated that antizyme-1 and its inhibitory protein, antizyme inhibitor, localize to centrosomes, and that alteration of their relative levels affect centriole amplification, thus contributing to oncogenesis [81]. Ectopic expression of antizyme was also implicated in activation of genes involved in DNA repair resulting in increased radio-resistance of these cells [82].…”

The benefits of local depletion: The centrosome as a scaffold for ubiquitin-proteasome-mediated degradation

“…It is also worth noting that centrosomal Mps1 is degraded by an ubiquitin-independent proteasomal degradation mechanism mediated by Antizyme, a highly conserved protein that localizes to the centrosome, binds non-ubiquitinated substrates and targets them to the proteasome for degradation. 50,51 Loss of Antizyme-mediated Mps1 degradation results in centrosome amplification and contributes to aberrant MTOC activity and subsequent aneuploidy in human melanomas. 52 Antizyme regulation of centrosome duplication via Mps1 degradation suggests diverse modes of proteasome-mediated degradation, including ubiquitin-independent proteolysis, are utilized by centrosome-associated proteasomes.…”