Molecular Basis of Terminal Cell Differentiation and Cellular Senescence

Cancer cells frequently display defects in cellular differentiation. Defining ways of correcting this defect and inducing terminal differentiation or cellular senescence in tumor cells offers potential for developing improved therapies for malignant diseases. Terminal cell differentiation and cellular senescence involve multiple parallel changes in gene expression that culminate in a loss of growth potential. To identify and define the functional consequences of these genomic changes we developed an 'overlapping pathway screening' approach involving screening of genetic information from cancer cells induced to terminally differentiate with genetic information from cells that have undergone senescence. Using this strategy we cloned human polynucleotide phosphorylase (hPNPaseold-35) an evolutionary conserved enzyme that promotes the degradation of mRNA, a template to make a specific protein. One target for this enzyme is the important cell cycle regulating gene c-myc. When put back into cells, hPNPaseold-35 degrades the c-myc mRNA reducing c-myc protein, thereby, causing cells to irreversibly growth arrest and undergo senescence. These studies suggest that hPNPaseold-35 is a direct regulator of cell growth and senescence. In this context, this gene may provide a unique target for altering growth of cancer cells and regulating senescence. Studies are focused on understanding this interesting enzyme and defining its targets in cells and to develop ways of using this gene to regulate senescence and differentiation.

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