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Identification of Novel Targets of the Human Cell Cycle Regulatory Protein Cdc34

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Annual rept. 1 Jul 97-30 Jun 98

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Normal human cells have developed an elaborate system to control cell division and the response to genetic damage. A characteristic feature of human malignancy is the loss of normal cell cycle control. CDC34 a gene essential for mitotic cell division in yeast encodes an enzyme required for degradation of yeast cell cycle regulators. The goal of this project is to understand the role of human Cdc34 in cell cycle transition in normal and malignant mammary cells. We have used a genetic assay called two-hybrid cloning to identify proteins that interact with mammalian Cdc34, screening 1.5 million human cDNAs. 30 cDNA clones found to be active in this assay have been isolated and are currently being analyzed. Surprisingly, four of these clones are known to be involved in the control of meiosis and spermatogenesis, while two belongs to a family of transcriptional repressors, and one has a distinct role in DNA double strand break repair. Thus, it appears from our studies that human Cdc34 may have a novel role in meiosis, recombination, transcription and response to DNA damage by specifically targeting these regulators for ubiquitination. Further studies are currently in progress to characterize the Cdc34-mediated regulation of these interactors and their physiological role in the cell cycle progression and development of breast cancer. This result will be critical to designing new therapeutic strategies that could modulate the activity of Cdc34 enzyme to prevent the growth and genesis of breast tumor.

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  • Genetic Engineering and Molecular Biology
  • Anatomy and Physiology
  • Medicine and Medical Research

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