| Gene information | Literature | Expression | lncRNA | Mutation | Homolog |
Basic Information | |
|---|---|
Gene ID | 993 |
Name | CDC25A |
Synonymous | cell division cycle 25A;CDC25A;cell division cycle 25A |
Definition | CDC25 isoform A1-CAG|CDC25A2-CAG isoform|M-phase inducer phosphatase 1|dual specificity phosphatase CDC25A |
Position | 3p21 |
Gene type | protein-coding |
Title | Abstract |
| Distinct modes of deregulation of the proto-oncogenic Cdc25A phosphatase in human breast cancer cell lines. | The rapid cell cycle arrest in response to DNA damage is mediated by degradation of the Cdc25A phosphatase, a proto-oncogene whose mRNA is frequently overexpressed in human tumours. Here, we study the occurrence and mechanisms of Cdc25A deregulation in human breast cancer cell lines. We demonstrate aberrantly elevated Cdc25A protein abundance and phosphatase activity in eight out of 15 cell lines, in some cases resulting in abrogation of the Cdc25A-mediated checkpoint response to ionizing radiation (IR), and this defect correlated with hypersensitivity to IR. Furthermore, we present evidence that deregulation of Cdc25A occurs predominantly on the post-transcriptional level, as overabundant Cdc25A protein was usually not accompanied by adequate mRNA overexpression. Instead, we demonstrate that aberrantly enhanced protein stability is an important mechanism underlying Cdc25A overabundance in a subset of breast cancer cell lines. Given the frequency of this mechanism, we propose that the DNA integrity checkpoint controlling Cdc25A protein stability might be a common target for deregulation in breast cancer. |
| Constitutive overexpression of CDC25A in primary human mammary epithelial cells results in both defective DNA damage response and chromosomal breaks at fragile sites. | CDC25A phosphatase, an essential component of the cell cycle machinery, is also a key player in integrating the specific signals of checkpoint control in response to DNA damage. There are several lines of evidence that indicate a role for CDC25A in cancer development, consistent with the fact that its overexpression is detected in human cancers. In particular we previously reported that CDC25A is overexpressed also in early breast carcinoma. Recent data suggest that oncogene activation during early stages of tumor development causes DNA replication stress resulting in the induction of DNA damage response (DDR) and that the selection of cells defecting in their DDR could lead to malignant progression. To address how CDC25A overexpression contributes to breast cancer development we established a cell model in which CDC25A was constitutively overexpressed in hTERT-immortalized primary human mammary epithelial cells. At the earliest passages following CDC25A transduction we observed DDR signs associated with unscheduled DNA replication origins. In the latest passages DDR was significantly impaired and, even after ionizing radiation exposition, cells failed to induce G1 and G2 checkpoints; moreover DNA replication stress conditions, such as aphidicolin treatment, highlighted increased fragile site breakages and destabilized chromosomes just in these latest passages cells. Our data suggest that CDC25A overexpression, pushing the cell through the cell cycle transitions, induces DDR alterations that might enhance genomic instability. |