Polo-like kinases and the microtubule organization center: targets for cancer therapies.
Studies from eukaryotic model systems, ranging from yeast to human, indicate that Polo and Polo-like kinases (Plks) are essential for the activity of the microtubule organization center. Polo/Plks localize to centrosomes or spindle pole bodies and undergo dramatic subcellular relocation during the cell cycle. Deregulated activities of Plks often result in abnormalities in centrosome duplication, maturation, and/or microtubule dynamics. Genetic and biochemical approaches have identified several candidate genes that either lie in the same pathway as POLO/PLKs or whose products are direct targets of Polo/Plks during the centrosome cycle. Recent studies have demonstrated that mammalian Plks also regulate the function of the Golgi complex, a cellular organelle closely associated with the centrosome and also having microtubule organization activity. Furthermore, deregulated expression of human PLK1 and PLK3 is strongly correlated with the development of many types of malignancies, and ectopic expression of kinase-active Plk3 or Plk1 dominant negative protein leads to rapid cell death. Given that several effective anti-tumor drugs directly interfere with microtubule dynamics, mammalian Plks are excellent targets for the development of anticancer drugs.
Molecular Carcinogenesis Laboratory, Department of Medicine, New York Medical College, Valhalla, NY 10595, USA.
Wei
W
Dai
John P
JP
Cogswell
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D018797:Cell Cycle Proteins / Q000819:agonists / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D006801:Humans; D022101:Microtubule-Organizing Center / Q000187:drug effects / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects / Q000502:physiology*; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D011494:Protein Kinases / Q000172:deficiency* / Q000187:drug effects / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D000097869:Polo-Like Kinase 1; D000097868:Polo-like Kinases
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D000097869:Polo-Like Kinase 1; C486256:PLK3 protein, human; D000097868:Polo-like Kinases