Disease relevance of CDC20

• In particular, CDC20 and MT2A represent a potential biomarker of human gastric cancer [1].
• We observed overexpression of CDC20 in several oral squamous cell carcinoma (OSCC) cell lines and primary head and neck tumors and provide evidence that such overexpression of CDC20 is associated with premature anaphase promotion, resulting in mitotic abnormalities in OSCC cell lines [2].
• HTLV-I Tax directly binds the Cdc20-associated anaphase-promoting complex and activates it ahead of schedule [3].
• Overexpression of Cdc20 leads to impairment of the spindle assembly checkpoint and aneuploidization in oral cancer [2].
• Identification of frequent impairment of the mitotic checkpoint and molecular analysis of the mitotic checkpoint genes, hsMAD2 and p55CDC, in human lung cancers [4].

High impact information on CDC20

• Bub1 directly phosphorylates Cdc20 in vitro and inhibits the ubiquitin ligase activity of APC/C(Cdc20) catalytically [5].
• Ectopic expression of the nonphosphorylatable Cdc20 mutant allows HeLa cells to escape from mitosis in the presence of spindle damage [5].
• Mad1 and Cdc20 contain Mad2 binding motifs that share a common consensus [6].
• Mad2 also undergoes a similar striking structural change upon binding to a Mad1 or Cdc20 binding motif peptide [6].
• The tumour suppressor RASSF1A regulates mitosis by inhibiting the APC-Cdc20 complex [7].

Biological context of CDC20

• Recent work has shown that activation of the APC in mitosis depends on CDC20, whereas APC is maintained active in G1 via association with the CDC20-related protein CDH1 [8].
• The anaphase-promoting complex activated by CDC20 and CDH1 is a major ubiquitination system that controls the destruction of cell cycle regulators [9].
• These mechanisms can explain the temporal order of APC activation by CDC20 and CDH1 and may help to ensure that exit from mitosis is not initiated before anaphase has occurred [10].
• In contrast, the analysis of phosphorylated and nonphosphorylated forms of CDC20 suggests that CDC20 phosphorylation is neither sufficient nor required for APC activation [10].
• BACKGROUND: Chromosome segregation and mitotic exit depend on activation of the anaphase-promoting complex (APC) by the substrate adaptor proteins CDC20 and CDH1 [11].

Anatomical context of CDC20

• We also reconstituted the chromosomal instability phenotype in a chromosomally stable OSCC cell line by overexpressing CDC20 [2].
• Some p55CDC is also associated with the spindle microtubules and spindle poles, and some is diffuse in the cytoplasm [12].
• Moreover, immunoprecipitation followed by Western blot analyses confirmed that native p55CDC is associated with BUBR1 in HeLa cells [13].
• There is also evidence to indicate that the spindle checkpoint components and Cdc20 are spatially regulated by the mitotic apparatus, in particular they are recruited to improperly attached kinetochores [14].
• The p55CDC protein appears to be essential for cell division, since transfection of antisense p55CDC cDNA into CHO cells resulted in isolation of only those cells which exhibited a compensatory increase in p55CDC transcripts in the sense orientation [15].

Associations of CDC20 with chemical compounds

• Spindle checkpoint activation by nocodazole treatment enhances the association between p55CDC and His6-BUBR1 [13].
• Mutation of a conserved lysine in this region weakened Cdc20 binding and correspondingly reduced checkpoint function [16].
• Based on this evidence, and by means of specific cell cycle modulators, such as nocodazole and hydroxyurea, we demonstrated that both TSA and NaBt were responsible for loss of p55CDC/Cdc20 expression, but with different mechanisms of action [17].
• Further, we have identified a unique polyhistidine motif with metal binding property adjacent to this second binding domain that may be important for maintaining the overall conformation of Cdc20 for its binding to Mad2 [18].
• We identified speriolin and determined that it is a novel spermatogenic cell-specific Cdc20-binding protein, is present in the cytoplasm, and is concentrated at the centrosomes of spermatocytes and spermatids and that a leucine zipper domain is required to target speriolin to the centrosome [19].

Physical interactions of CDC20

• Mad2 is a component of the SAC effector complex that sequesters Cdc20 to halt anaphase [20].
• Conversely depletion of RABP1 by RNA interference prevented both the localization of RASSF1A to the spindle poles as well as its binding to Cdc20, resulting in premature destruction of mitotic cyclins and acceleration of mitotic progression [21].
• The spindle checkpoint protein Mad2 inhibits the activity of APC/C through direct binding to its activator Cdc20 [22].

Enzymatic interactions of CDC20

• Upon checkpoint activation, Bub1 itself is hyperphosphorylated and its kinase activity toward Cdc20 is stimulated [5].

Regulatory relationships of CDC20

• The ordered activation of the ubiquitin protein ligase anaphase-promoting complex (APC) or cyclosome by CDC20 in metaphase and by CDH1 in telophase is essential for anaphase and for exit from mitosis, respectively [10].
• Polo-like kinase-1 is required for bipolar spindle formation but is dispensable for anaphase promoting complex/Cdc20 activation and initiation of cytokinesis [23].

Other interactions of CDC20

• Mitotic regulation of the APC activator proteins CDC20 and CDH1 [10].
• Most importantly, we show that Nek2A binds directly to the APC/C, also in an MR-dependent manner, even in the absence of the adaptor protein Cdc20 [24].
• In tax-expressing cells, the Cdc20-associated anaphase promoting complex (APC(Cdc20)), an E3 ubiquitin ligase that controls metaphase to anaphase transition, becomes active before cellular entry into mitosis as evidenced by premature cyclin B1 polyubiquitination and degradation during S/G(2) [3].
• Consistent with the notion that Tax activates APC(Cdc20) directly, Tax is found to coimmunoprecipitate with Cdc20 and Cdc27/APC3 [3].
• APC activation by CDH1 depends on a conserved C-terminal motif that is also found in CDC20 and APC10 [11].

Analytical, diagnostic and therapeutic context of CDC20

• Western blotting and immunohistochemical analyses for CDC20 and SKB1 showed overexpression and localization changes of the corresponding protein in human gastric cancer tissues [1].
• Microinjection of anti-p55CDC antibody into mitotic mammalian cells induces arrest or delay at metaphase, and impairs progression of late mitotic events [12].
• Immunofluorescence studies and expression of a p55CDC-GFP chimera demonstrate that p55CDC is concentrated at the kinetochores in M phase cells from late prophase to telophase [12].
• The WD repeats of the Bub3 and Cdc20 kinetochore proteins are important for the physical interactions of these proteins with Mad2 and BubR1 to yield a kinetochore protein complex capable of delaying anaphase by inhibiting ubiquitin ligation via the anaphase-promoting complex/cyclosome [25].
• Immunoprecipitation of p55CDC yielded protein complexes with kinase activity which fluctuated during the cell cycle [15].

References