Identification of a Sequence Element from p53 that Signals for Mdm2-targeted Deg
Summary Research at Harvard University has led to a novel means of protecting the cell against oncogenic tumor formation. This invention provides compositions and methods for inhibiting degradation of tumor suppressor protein p53, thereby enhancing p53-mediated growth-suppressive properties. This technology shows particular promise in gene therapy applications.
The p53 protein is a transcription factor involved in the control of cell cycle progression, DNA integrity, and the survival of cells exposed to DNA damaging agents. Activation of p53 generally results in cycle arrest, a critical step towards the repair of cells with genomic mutations that may result in cellular transformation. Loss of p53 activity, therefore, predisposes cells to the acquisition of oncogenic mutations.
Oncoproteins Mdm2 and E6 both inactivate p53 tumor suppressor activity by promoting p53 degradation. Unusually high levels of Mdm2 are found in many tumor types with wild type p53, and the human papillomavirus E6 protein is etiologically involved in the development of cervical cancer.
Use and Advantages
A seven (7) amino acid sequence element from p53 that functions as a degradation signal for both the Mdm2 and human papillomavirus E6 oncoproteins has been pinpointed. A small peptide derived from the degradation signal sequence of p53 can efficiently block Mdm2- and E6-mediated degradation of p53. Inhibition of p53 degradation will result in an increase of p53 protein levels and therefore restore its tumor suppressor function.
Applications Both peptide delivery and gene therapy represent promising venues for developing this technology . In one embodiment, delivery of these peptides by either anti-Mdm2 or anti-E6 antibody tagged liposome-mediated transfer will selectively kill the cancer cells and have no effect on normal cells. For Further Information Please Contact the Director of Business Development Vivian Berlin Email: firstname.lastname@example.org Telephone: (617) 495-0474
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