New gene therapy study findings have been reported from Cleveland Clinic

   "To study the role of cyclin D1 in driving human mammary cell transformation, we expressed a constitutively active cyclin D1-CDK fusion protein (D1/CDK) in immortalized human mammary epithelial cells. D1/CDK-expressing human mammary epithelial cells grew anchorage-independently in the presence of wild-type p53, consistent with the idea that D1/CDK disrupts downstream p53 signaling. Using this transformation model, we examined the sensitivity of the D1/CDK-expressing cells to Nutlin-3, an HDM2 antagonist that activates p53. Surprisingly, treatment of D1/CDK-transformed cells with Nutlin-3 prevented their anchorage-independent growth. The Nutlin-3-induced growth arrest was enforced in D1/CDK-expressing cells despite the presence of hyperphosphorylated RB implicating a p53-dependent, RB-independent mechanism for growth suppression. Further analysis identified that CDC2 and cyclin B1, key cell cycle regulators, were stably down-regulated following p53 stabilization by Nutlin-3, consistent with direct interaction between p53 and the CDC2 and cyclin B1 promoters, leading to the repression of transcription by methylation. In contrast to D1/CDK expression, direct inactivation of p53 resulted in no repression of CDC2 and no cell cycle arrest," wrote C.E. Kan and colleagues, Cleveland Clinic.

   The researchers concluded: "We conclude that induction of p53 by Nutlin-3 is a viable therapeutic strategy in cancers with constitutive CDK signaling due to the direct repression of specific p53 target genes."

   Kan and colleagues published their study in Cancer Research (P53-mediated growth suppression in response to Nutlin-3 in cyclin D1-transformed cells occurs independently of p2l. Cancer Research, 2007;67(20):9862-9868).

   For additional information, contact M.W. Jackson, Cleveland Clinic, Dept. of Molecular Genetics, Lerner Research Institute, NE20, 9500 Euclid Avenue, Cleveland, OH 44195, USA.

   The publisher of the journal Cancer Research can be contacted at: American Association Cancer Research, 615 Chestnut St., 17TH Floor, Philadelphia, PA 19106-4404, USA.

   Keywords: United States, Cleveland, Biotechnology, Cancer, Cancer Research, Gene Therapy, Oncology, Proteomics. Fusion Proteins, Cleveland Clinic.

   This article was prepared by Clinical Oncology Week editors from staff and other reports. Copyright 2007, Clinical Oncology Week via NewsRx.com.

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