Id-1 promotes chromosomal instability through modification of APC/C activity during mitosis in response to microtubule disruption.
Id-1 (Inhibitor of DNA binding/differential-1) plays a positive role in tumorigenesis through regulation of multiple signaling pathways. Recently, it is suggested that upregulation of Id-1 in cancer cells promotes chromosomal instability. However, the underlying molecular mechanism is not known. In this study, we report a novel function of Id-1 in regulation of mitosis through physical interaction with Cdc20 (cell division cycle protein 20) and Cdh1 (Cdc20 homolog 1). During early mitosis, Id-1 interacts with Cdc20 and RASSF1A (Ras association domain family 1A), leading to enhanced APC(Cdc20) activity, which in turn promotes cyclin B1/securin degradation and premature mitosis. During late mitosis, Id-1 binds to Cdh1 and disrupts the interaction between Cdh1 and APC, resulting in suppression of APC(Cdh1) activity. On the other hand, overexpression of Cdh1 leads to Id-1 protein degradation, suggesting that Id-1 may also act as a substrate of APC(Cdh1). The negative effect of Id-1 on APC(Cdh1) results in suppression of APC(Cdh1)-induced Aurora A and Cdc20 degradation, leading to failure in cytokinesis. As a result, overexpression of Id-1 in human prostate epithelial cells leads to polyploidy in response to microtubule disruption, and this effect is abolished when Id-1 expression is suppressed using antisense technology. These results demonstrate a novel function of Id-1 in promoting chromosomal instability through modification of APC/C activity during mitosis and provide a novel molecular mechanism accounted for the function of Id-1 as an oncogene.
Wang
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Cancer Biology Group, Department of Anatomy, Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China. xhwang@hkucc.hku.hk
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Zhang
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Leung
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D064173:Anaphase-Promoting Complex-Cyclosome; D064127:Aurora Kinases; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins / Q000502:physiology*; D002460:Cell Line; D043171:Chromosomal Instability; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D016193:G1 Phase; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000502:physiology*; D008870:Microtubules / Q000502:physiology*; D008938:Mitosis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000502:physiology; D025801:Ubiquitin / Q000378:metabolism; D043743:Ubiquitin-Protein Ligase Complexes / Q000502:physiology*
C534699:CCNB1 protein, human; D064199:Cdc20 Proteins; D018797:Cell Cycle Proteins; D019926:Cyclin B; D056744:Cyclin B1; D051798:Inhibitor of Differentiation Protein 1; C411762:RASSF1 protein, human; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; C577488:CDC20 protein, human; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases