An Overview of CDC7
CDC7, a serine / threonine kinase, was first found in Saccharomyces cerevisiae. The gene is an open reading frame that encodes 574 amino acid length proteins and contains four conserved regions. After CDC7-ASK is formed in the nucleus, phosphorylation activates and binds to multiple members of the MCM (minichromosome maintenance complex) family on chromosomes, such as MCM2, MCM4, MCM6. The phosphorylation of MCM2 is the strongest. The activated MCM2 may remove the inhibition of helicase through the change of spatial conformation and further promote the initiation of DNA replication.
Inhibition of CDC7
With the development of biopharmaceutical technology, CDC7 kinase inhibitor, PHA-767491, which has low molecular weight and good solubility, has been developed. Montagnoli and others have developed CDC7 kinase inhibitors. The inhibition rate of CDC7 gene was as high as 65%. PHA-767491 showed a combined inhibitory effect on CDC7 and Cdk9 in a variety of human tumor cell lines. PHA-767491 did not affect the cell activity of human skin fibroblasts, indicating that PHA-767491 was selective. Another CDC7 inhibitor, NMS-354, which acts only on tumor cells and is harmless to normal cells. NMS-354 can induce apoptosis in multiple tumor cells through a p53 independent pathway.
CDC7 and diseases
The overexpression of CDC7 and its regulatory protein Dbf4 found in many human tumor cell lines, such as the overexpression of CDC7 in ovarian cancer cells, suggests that the tumor stage is late and the prognosis is poor. In addition, CDC7 and Dbf4 are overexpressed in malignant melanoma, and the higher the expression level, The shorter the recurrence free survival time of the patient. Overexpression of phosphorylated MCM2 found in many human malignant tumor cells suggests an increase in CDC7 kinase activity, including DLB-CL and Hodgkin's lymphoma. As CDC7 is necessary for DNA replication, the increased expression of CDC7 is positively correlated with the proliferation activity of tumor cells. However, the expression level of CDC7 was not related to cell proliferation, but related to the proportion of S phase cells. The overexpression of CDC7 and Dbf4 resulted in cell cycle arrest in S phase, which participated in the repair of DNA damage and promoted the survival of tumor cells. Mutations in CDC7 gene have been found in human gastric and colon cancer cells. Overexpression of DC7 / Dbf4 leads to mass survival of tumor cells.
Hou Yun, Fu Kai, Wang Huaqing.The role of CDC 7 MCM 2 in prognosis and treatment of diffuse large B cell lymphoma [J]. Clinical Oncology in China 2013! 40 (11): 678-681