Cancer : Establishing metastasis

Human VRK1 Is an Early Response Gene and Its Loss Causes a Block in Cell Cycle Progression??

In mammalian cells, the regulatory proteins that control the cell cycle are necessary due to the requirements of living in a heterogeneous environment of cellular interactions and growth factors. VRK1 is a new serine-threonine kinase that phosphorylates several transcription factors and is associated with proliferation phenotypes.

Scientists have discovered that a protein called VRK1 could help cancer take root in new parts of the body. It was discovered that VRK1 is necessary for the mesenchymal to epithelial transition, which scientists suspect may be important for the establishment of metastases. The expression of the VRK1 gene is activated by the addition of serum to the cells deprived of food, which indicates that it is required for the exit of the G0 phase and the entry in G1; a response that parallels the re-expression of MYC, FOS and CCND1 genes (cyclin D1), suggesting that VRK1 is an early response gene. The expression of the VRK1 gene is also closed by serum extraction.

The promoter of the human VRK1 gene cloned in a luciferase reporter responds similarly to serum. In response to serum, the expression level of the VRK1 protein has a positive correlation with cell proliferation markers such as phosphorylated Rb or PCNA, and is inversely correlated with cell cycle inhibitors such as p27. Removal of VRK1 by siRNA results in a G1 block in cell division and in the loss of phosphorylated Rb, cyclin D1 and other proliferation markers. The elimination of VRK1 by siRNA induces a reduction of cell proliferation. VRK1 is colocalized with p63 in proliferating areas of squamous epithelium and identifies a subpopulation in the basal layer.

They observed that cells with high levels of VRK1 were more apt to form cell-to-cell connections and had lower levels of mesenchymal markers that are often present in cancer cells. On the contrary, the cells seemed to undergo the opposite transition, from mesenchymal to epithelial. The cells were much less likely to migrate. If high levels of VRK1 caused cancer cells to migrate more slowly, perhaps VRK1 was necessary to allow cells to colonize a new area of the body.

Significance

VRK1 is an immediate early response gene required for entry into G1, and due to its involvement in normal cell proliferation and division, it could be a new target for the development of inhibitors of cell proliferation. In addition, VRK1 may one day serve as a biomarker for aggressive cancers, which could inform oncologists as they decide on more advanced or conservative treatments.