ABSTRACT
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.
Subject(s)
Cell Cycle Proteins/physiology , Chromosomal Instability , Inhibitor of Differentiation Protein 1/physiology , Microtubules/physiology , Mitosis , Ubiquitin-Protein Ligase Complexes/physiology , Anaphase-Promoting Complex-Cyclosome , Aurora Kinases , Cdc20 Proteins , Cell Line , Cyclin B/metabolism , Cyclin B1 , G1 Phase , Humans , Protein Serine-Threonine Kinases/metabolism , Tumor Suppressor Proteins/physiology , Ubiquitin/metabolismABSTRACT
AIMS: Epidermal growth factor receptor (EGFR) is suggested as one of the positive regulators in the invasive progression of renal cell cancer (RCC). Recently, Id-1 (inhibitor of differentiation or DNA binding), a helix-loop-helix transcription factor, has been identified as one of the key factors in the EGFR signalling pathway. The aim of this study was to investigate the significance of Id-1 expression in renal cell cancer and to study its relationship with EGFR. METHODS AND RESULTS: Id-1 and EGFR expression was examined in tissue microarray (TMA) samples of 107 RCC and 32 normal kidney specimens by immunohistochemistry. Relative Id-1 and EGFR protein expression was quantified by estimating the staining intensity on a four-grade scale. We found that while negative to weak expression of Id-1 and EGFR was observed in non-malignant kidney tissues, most RCCs showed significant positive Id-1 and EGFR expression in tumour cells. In addition, Id-1 immunostaining intensity was positively associated with increased tumour staging, grading and EGFR expression. CONCLUSION: Overexpression of Id-1 is a novel marker for advanced RCC which is positively correlated with EGFR expression. Our results suggest that Id-1 may play an important role in the development of RCC and indicate that Id-1 is a potential marker of patients with a poor prognosis.
