Friday 27 January 2017
Definition: Serine/threonine kinase PLK4 also known as polo-like kinase 4 is an enzyme that in humans is encoded by the PLK4 gene. The Drosophila homolog is SAK, the C elegans homolog is zyg-1, and the Xenopus homolog is Plx4.
PLK4 encodes a member of the polo family of serine/threonine protein kinases / SLKs .
Overexpression of PLK4 results in centrosome amplification, and knockdown of PLK4 results in loss of centrosomes.
- Centrosome amplification is a common feature of human tumors, but whether this is a cause or a consequence of cancer remains unclear.
- The consequence of centrosome amplification have been tested by creating mice in which centrosome number can be chronically increased in the absence of additional genetic defects.
- Increasing centrosome number elevated tumor initiation in a mouse model of intestinal neoplasia.
- Supernumerary centrosomes are sufficient to drive aneuploidy and the development of spontaneous tumors in multiple tissues.
- Tumors arising from centrosome amplification exhibit frequent mitotic errors and possess complex karyotypes, recapitulating a common feature of human cancer.
- These data support a direct causal relationship among centrosome amplification, genomic instability, and tumor development.
Inhibitors of the enzymatic activity PLK4 have potential in the treatment of cancer. The PLK4 inhibitor R1530 down regulates the expression of mitotic checkpoint kinase BubR1 that in turn leads to polyploidy rendering cancer cells unstable and more sensitive to cancer chemotherapy. Furthermore, normal cells are resistant to the polyploidy inducing effects of R1530.
Another PLK4 inhibitor, CFI-400945 has demonstrated efficacy in animal models of breast and ovarian cancer.
Another PLK4 inhibitor, centrinone, has been reported to deplete centrioles in human and other vertebrate cell types, which resulted in a p53-dependent cell cycle arrest in G1.
Inhibition of PLK4 using a chemical genetic strategy has validated this p53-dependent cell cycle arrest in G1.