Molecular Regulation of the Enzyme Telomerase in Cancer

Download or read book Molecular Regulation of the Enzyme Telomerase in Cancer written by Julie Margherita Dwyer and published by . This book was released on 2009 with total page 352 pages. Available in PDF, EPUB and Kindle. Book excerpt: The present study investigates the roles of the Ets TFs, Ets-1 and Ets-2, in the regulation of telomerase in breast cancer. Ets-mediated gene regulation leads to transcription of a plethora of genes, including c-Myc which stimulates telomerase activity. Thus complex positive and negative regulation involving both Ets-2 and c-Myc signalling events may regulate telomerase activity. Examination of telomerase activity, after selective silencing of Ets-1 or Ets-2 in breast cancer cell lines, has revelaed that Ets-2, but not Ets-1, is specifically required for telomerase activity in several breast cancer lines. Gene knockdown of Ets-2 is associated with compromised telomerase activity in correlation with decreased hTERT gene expression and reduced expression of the proto-oncogene c-Myc, a positive regulator of hTERT. Moreover, gene silencing of Ets-2 is suggested to mediate down-regulation of telomerase by two Ets consensus binding sites on the hTERT promoter. Silencing of Ets-2 to inhibit telomerase activity also induced breast cancer cell death in a manner partially dependent on hTERT gene expression. Thus Ets-2 appears to be required for telomerase activity and breast cancer cell survival through both direct and indirect regulation of hTERT gene transcription. Post-transcriptional modifications of hTERT are also required for full activation of the telomerase enzyme. The tumour suppressor PTEN has been reported to inhibit telomerase activity by lipid phosphatase function to suppress PI3K-Akt cell survival signalling, though the underlying mechanisms have not been fully explored. In this study, the role of PTEN in the regulation of telomerase in PTEN-null telomerase-positive HeLa cancer cells was examined. It was demonstrated that PTEN-induced inhibition of telomerase involves PTEN lipid phosphatase activity as suggested by the finding that PTEN lipid phosphatase activity disabled mutants have reduced capacity to inhibit telomerase activity. Telomeric DNA was identified as a possible novel interacting partner of PTEN. Thus it is possible that PTEN is required for inhibition of telomerase activity through interaction with telomeres in the nucleus. It is hypothesised that the interaction of PTEN with telomeres interferes with access of telomerase and thereby inhibits lengthening actions of telomerase. Further investigations are required to establish the functions of PTEN interaction with telomeres in telomerase repression and cell immortalisation during cancer development.