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Role of Cyclin D1 and cdk Inhibitors in Breast Cancer Pathogenesis

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Annual summary rept. 30 Sep 2000-29 Sep 2001

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PI3K signaling is involved in many aspects of cell cycle progression and is often deregulated in malignant cells. Akt, a downstream kinase effector of PI3K, stabilizes cyclin Dl protein and phosphorylates the cdk inhibitor p21 preventing its anti-proliferative effects in breast cancer cells. In this report we attempt to identify PI3K- dependent molecules necessary to rescue cyclin A expression. We examined if loss of p27 together with forced expression of cyclin Dl was sufficient to rescue cyclin A expression in p27-null MEFs and demonstrated that S phase entry could not be restored by forced cyclin Dl expression. As it has been reported that the cyclin A promoter contains a cyclic AMP responsive element and that Akt phosphorylates Ser-133 of CREB in response to mitogens, we examined the phosphorylation state of CREB in the presence or absence of LY. No significant differences in CREB activation were observed suggesting additional transcription factors are required for PI3K effects on cyclin A transcription. Lastly, examination of the activation of cyclin A promoter in MEFs with constitutively active Akt or p70S6 kinase suggests that constitutively active p70 is sufficient to rescue cyclin A promoter activity after inhibition of PI3K.

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  • Biochemistry
  • Genetic Engineering and Molecular Biology
  • Medicine and Medical Research

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