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Regulation of hTERT Expression and Function in Newly Immortalized p53(+) Human Mammary Epithelial Cell Lines

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Annual rept. 1 Jun 2006-31 May 2007

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Telomerase is reactivated in almost all human breast cancers loss of telomeric protection can lead to genomic instability. This proposal is to study telomerase reactivation and telomere protection in newly immortal, p53 human mammary epithelial cells HMEC, and to determine if these cells may be especially sensitive to therapies that target telomerase activity and telomere protection. Prior work showed that p53 can suppress most, but not all, telomerase expression in newly immortal p53 HMEC lines until telomeres become extremely short, when an unknown mechanism termed conversion relieves this repression. We hypothesized that the observed upregulation of cyclin-dependent kinase inhibitor p57 might protect cells with critically short telomeres by inhibiting growth until there is sufficient telomerase to protect the telomeric ends. Our research in the past year supports a role of p57 in arresting growth prior to a p53-mediated DNA damage response being evoked, as well as a novel role in telomere homeostasis. Inhibition of p57 produced a result similar to inhibition of telomerase - accelerated, complete growth arrest without telomerase reactivation. Unlike telomerase inhibition, p57 inhibition led to a p53- mediated DNA damage arrest. Our data support a potential role for inhibition of p57 andor telomerase in preferentially killing newly immortal p53 HMEC.

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  • Anatomy and Physiology
  • Medicine and Medical Research

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