Increased Expression and Activity of CDC25C Phosphatase and an Alternatively Spliced Variant in Prostate Cancer

Abstract

Alterations in the control of cell cycle progression have been implicated in a wide variety of malignant neoplasms, including prostate cancer. CDC25 phosphatases belong to the tyrosine phosphatase family and play a critical role in regulating cell cycle progression by dephosphorylating cyclin-dependent kinases at inhibitory residues. CDC25C plays an important role in the G 2 -M transition by activating Cdc2/Cyclin B1 complexes. To determine whether CDC25C activity is altered in prostate cancer, we have examined the expression of CDC25C and an alternatively spliced variant in human prostate cancer samples and cell lines. CDC25C protein is up-regulated in prostate cancer in comparison with normal prostate tissue and is present almost exclusively in its active dephosphorylated form. Expression of a biologically active alternatively spliced CDC25C isoform is also increased in prostate cancer and expression of alternatively spliced CDC25C is correlated to occurrence of biochemical (prostate-specific antigen) recurrence. We have also developed a quantitative reverse transcriptase-PCR analysis of Ki-67 expression as a method of measuring proliferative activity in prostate cancer from RNA samples. Based on this analysis of Ki67 expression, some but not all of this increase in CDC25C and its alternatively spliced variants is correlated with increased proliferation in prostate cancer. This data suggests that CDC25C might play an important role in prostate cancer progression and could be used to monitor and predict the aggressiveness of this disease.Abnormal expression and/or activity of cell cycle regulatory proteins have been identified in a wide variety of malignant neoplasms, including prostate cancer. Cell cycle progression is controlled by the sequential activities of cyclin-dependent kinases, whose activities are tightly regulated by cyclins, cyclin-dependent kinase inhibitors, and a variety of other proteins. Several groups have shown increased expression of cyclin B1, which plays a critical role in the G 2 -M transition, in human prostate cancers (1, 2). Recent work by Maddison et al. (3) has shown increased levels of cyclin B1 in poorly differentiated and androgen-independent prostate cancers in the TRAMP mouse model of prostate cancer. During G 2 , the Cdc2/Cyclin B complex is kept inactive by phosphorylation of Cdc2 by Wee1. At the onset of mitosis, Cdc2/Cyclin B complexes are dephosphorylated by CDC25 phosphatase leading to increased kinase activity (4 -6). Our laboratory has shown previously that disruption of fibroblast growth factor signaling in prostate cancer cells leads to decrease in Cdc2 kinase activity and arrest in G 2 followed by cell death (7). These findings imply that the G 2 -M transition may be a critical checkpoint in prostate cancer.CDC25 phosphatases belong to the tyrosine phosphatase family and play a critical role in regulating cell cycle progression by dephosphorylating cyclin-dependent kinases at inhibitory residues. In human cells, CDC25 proteins are encoded by a multigene fa...

CDK1 promotes cell proliferation and survival via phosphorylation and inhibition of FOXO1 transcription factor

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Androgen receptor phosphorylation and stabilization in prostate cancer by cyclin-dependent kinase 1

“…Interestingly, we have found that the most highly overexpressed cell-cycle-regulatory genes in androgen-independent PCa are Cdk1, cyclin B1, and cyclin B2 (3.3, 2.7, and 2.6-fold increases in median expression, respectively), with the cyclin B1 increase being statistically significant (6). Previous studies have also found increased expression of cyclin B1 and Cdc25 in PCa, and this has been associated with more aggressive PCa and progression to androgen-independent PCa (39)(40)(41). Based on these observations, we examined androgen-independent PCa cells to determine whether Cdk1 may mediate enhanced responses to low levels of androgen.…”

Induction of the adenoma-carcinoma progression and Cdc25A-B phosphatases by the trefoil factor TFF1 in human colon epithelial cells

“…Splicing isoforms can also arise from noncancer cells in the tumor stroma, including endothelial, mesenchymal, and immune components. In human solid tumors of the colon and prostate, alternatively spliced Cdc25s variants correlated with agressive disease, recurrence and differentiation (Hernandez et al, 2001;Ozen and Ittmann, 2005). Molecular identification and functional …”