Dominant-negative polo-like kinase 1 induces mitotic catastrophe independent of cdc25C function

• Published in: Cell growth & differentiation Vol. 11; no. 12; pp. 615 - 623
• Main Authors: COGSWELL, John P, BROWN, Chadwick E, BISI, John E, NEILL, Suzanne D
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.12.2000
• Subjects: Adenoviridae - genetics; Biological and medical sciences; Blotting, Western; Breast - metabolism; cdc25 Phosphatases - genetics; cdc25 Phosphatases - physiology; Cell Cycle Proteins - genetics; Cell Death; Cell physiology; Cell Separation; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Epithelial Cells - metabolism; Female; Fibroblasts - metabolism; Flow Cytometry; Fundamental and applied biological sciences. Psychology; Genes, Dominant - genetics; HeLa Cells; Humans; Immunohistochemistry; Microscopy, Fluorescence; Mitosis - genetics; Molecular and cellular biology; Phosphorylation; Polo-Like Kinase 1; Protein Kinases - genetics; Protein Kinases - physiology; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Time Factors; Tumor Cells, Cultured; Xenopus Proteins - genetics; Xenopus Proteins - physiology; Phosphorylation; Adenoviridae; Enzyme; Mitosis; Phosphoprotein phosphatase; Transferases; Phosphoric monoester hydrolases; Esterases; Malignant tumor; Gene expression; Virus; Cell line; Osteosarcoma; Protein kinase; Cell cycle; Hydrolases; Apoptosis
• ISSN: 1044-9523; 2377-0732

Polo-like kinase 1 (PLK1), which has been shown to have a critical role in mitosis, is one possible target for cancer therapeutic intervention. PLK1, at least in Xenopus, starts the mitotic cascade by phosphorylating and activating cdc25C phosphatase. Also, loss of PLK1 function has been shown to induce mitotic catastrophe in a HeLa cervical carcinoma cell line but not in normal Hs68 fibroblasts. We wanted to understand whether the selective mitotic catastrophe in HeLa cells could be extended to other tumor types, and, if so, whether it could be attributable to a tumor-specific loss of dependence on PLK1 for cdc25C activation. When PLK1 function was blocked through adenovirus delivery of a dominant-negative gene, we observed tumor-selective apoptosis in most tumor cell lines. In some lines, dominant-negative PLK1 induced a mitotic catastrophe similar to that published in HeLa cells (K. E. Mundt et al., Biochem. Biophys Res. Commun., 239: 377-385, 1997). Normal human mammary epithelial cells, although arrested in mitosis, appeared to escape the loss of centrosome maturation and mitotic catastrophe seen in tumor lines. Mitotic phosphorylation of cdc25C and activation of cdk1 was blocked by dominant-negative PLK1 in human mammary epithelial cells as well as in the tumor lines regardless of whether they underwent mitotic catastrophe. These data strongly argue that the mitotic catastrophe is not attributable to a lack of dependence for PLK1 in activating cdc25C.