Phosphatases and kinases regulating CDC25 activity in the cell cycle: clinical implications of CDC25 overexpression and potential treatment strategies

Abstract

Alterations in the cell cycle regulatory genes result in uncontrolled cell proliferation leading to several disease conditions. Cyclin-dependent kinases (CDK) and their regulatory subunit, cyclins, are essential proteins in cell-cycle progression. The activity of CDK is regulated by a series of phosphorylation and dephosphorylation at different amino acid residues. Cell Division Cycle-25 (CDC25) plays an important role in transitions between cell cycle phases by dephosphorylating and activating CDKs. CDC25B and CDC25C play a major role in G2/M progression, whereas CDC25A assists in G1/S transition. Different isomers of CDC25 expressions are upregulated in various clinicopathological situations. Overexpression of CDC25A deregulates G1/S and G2/M events, including the G2 checkpoint. CDC25B has oncogenic properties. Binding to the 14-3-3 proteins regulates the activity and localization of CDC25B. CDC25C is predominantly a nuclear protein in mammalian cells. At the G2/M transition, mitotic activation of CDC25C protein occurs by its dissociation from 14-3-3 proteins along with its phosphorylation at multiple sites within its N-terminal domain. In this article, we critically reviewed the biology of the activation/deactivation of CDC25 by kinases/phosphatases to maintain the level of CDK–cyclin activities and thus the genomic stability, clinical implications due to dysregulation of CDC25 and potential role of CDC25 inhibitors in diseases.

The Expression and Clinical Outcome of pCHK2-Thr68 and pCDC25C-Ser216 in Breast Cancer

“…Notably, dysregulated CDC25 has been implicated in various cancers such as ovarian and vulvar carcinoma due to induced genomic instability [10,13]. In this study, we detected the expression of pCHK2-Thr68 and pCDC25C-Ser216 in both breast cancer and paracancerous tissues using immunohistochemistry and explored their associations with breast cancer metastasis.…”

“…Among several proteins involved in cell division, the highly regulated cell division cycle 25 (CDC25) phosphatase is regarded as a key component in ensuring normal cell division and genomic integrity [9,10]. CDC25 phosphatase activates cyclin-dependent kinase (CDK)–cyclin complexes and regulates cell cycle progression by driving G1-S/G2-M transitions during mitosis.…”

“…In response to DNA damage, inhibitory checkpoint kinase (CHK) phosphorylates CDC25 and inhibits its activities, leading to cell cycle arrest. Moreover, the halted cell cycle allows the cell to repair DNA before replication or alternatively undergo apoptosis [9,10]. It is therefore conceivable that dysfunction of these regulatory proteins can result in the accumulation of mutations over time and subsequently contribute to tumorigenesis.…”

“…It is gradually recognized that the regulation of CDC25C expression in response to DNA damage in cancer cells involves complex processes that are yet to be explored (e.g., alterative splicing) [14]. In addition, CDC25C may be related to the breast cancer due to the potential roles of CDC25C and pCDC25C (Ser216) in certain cancer pathways in women (e.g., vulvar carcinomas) [10,13]. Considering the possible underrated measurement of CDC25C expression in most studies and the prospective involvement of CDC25C in female cancers, we focus our priorities on CDC25C in the carcinogenesis of breast cancer.…”

Physiology and Pathology of Autoimmune Diseases: Role of CD4+ T cells in Rheumatoid Arthritis

“…The dual-speciicity phosphatase cell division cycle 25 B (CDC25B) positively regulates cell proliferation by promoting G2/M transition [98]. Recently, our group has found a reduced expression of this phosphatase in CD4 T cells of patients diagnosed with early arthritis [99].…”