Cyclin E deregulation alters the biologic properties of ovarian cancer cells.
We have previously shown that the low molecular weight (LMW) forms (trunk 1 and trunk 2) of cyclin E are biochemically hyperactive and induce G1/S progression in normal epithelial cells. Here we investigate the biologic consequences of LMW cyclin E expression in ovarian cancer cells. Using a panel of ovarian carcinoma tumors we find that cyclin E overexpression is invariably due to the presence of LMW forms and that expression of these forms appears to correlate with more advanced grade and stage of disease. Despite similar expression of p21 and p27, cyclin E overexpressing tumors have higher kinase function. Using an isogenic ovarian cancer model, we find that clones that overexpress the trunk 1 (T1) protein have a 10-fold increase in cyclin E kinase function, a 20% increase in S-phase fraction, a 10-15% decrease in doubling time and a 20% increase in colony formation compared to parental cells that express only the FL cyclin E protein. T1 clones were resistant to G1 arrest but more sensitive to cisplatin. Therefore, in ovarian tumors, the presence of LMW cyclin E forms confers altered biologic properties. Our data provides a potential mechanism for the poor prognosis of patients with LMW cyclin E expressing tumors.
Department of Surgical Oncology, MD Anderson Cancer Center, University of Texas, Houston, TX 77030, USA.
Isabelle
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Bedrosian
Karen H
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Claire
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Verschraegen
Khandan
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Keyomarsi
D015153:Blotting, Western; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D002455:Cell Division; D045744:Cell Line, Tumor; D004396:Coloring Agents / Q000494:pharmacology; D019927:Cyclin E / Q000096:biosynthesis* / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016213:Cyclins / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D016193:G1 Phase; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007700:Kinetics; D008148:Lovastatin / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism; D011233:Precipitin Tests; D016196:S Phase; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D004396:Coloring Agents; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D013778:Tetrazolium Salts; D013844:Thiazoles; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D008148:Lovastatin; C022616:thiazolyl blue