P53-Dependent Asymmetric Cell Division - A Novel Screen for Growth Regulatory Compounds
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Somatic stem cells possess the ability to express a number of different cellular programs including proliferation, differentiation, quiescence, and renewal. In the renewal program, an example of linear growth, cells divide asymmetrically. One daughter cell retains the mitotic capacity of the parent stem cell. The other daughter cell either differentiates to become a non-dividing, short-lived tissue constituent or divides to produce descendants that undergo a limited number of divisions before becoming post-mitotic non-dividing cells. Proliferation (exponential growth) involves a dividing cell giving rise to two daughter dividing cells.
Because of linear growth kinetics, it is impractical to maintain primary cells in culture for more than 20-30 culture passages. The "p53 conditional" cell lines allow for analysis of normal stem cell division without the need for primary tissue cells.
Fox Chase researchers have developed murine cell lines that divide with either exponential (like transformed cancer cells) or linear (like normal tissue stem cells) population growth kinetics. The conditional division properties are dependent of zinc-controlled expression of wild-type p53 in cells devoid of endogenous p53 protein.
Applications and Advantages:
The p53 conditional division cell lines constitute a unique screen for anti-cancer compounds. Existing cell line panels for this purpose use primary tissue cells (e.g. bone marrow cells) to control for effects of test compounds in various tumor-derived cells. Because of myriad differences between these control cells and the test cells, screening cell panels in present use are quite poor for identifying compounds that selectively affect cell division mechanisms. The conditional division cell lines allow the comparison of screens of the same cells in either a cancer-like growth state or in a normal growth state. Such screens should reveal highly selective compounds that interfere specifically with cancer cell division but not normal cell division.
Because the disruption of stem cell division kinetics is a general feature of diseases that are due to increased cell proliferative (e.g. psoriasis), comparative screens with the conditional cell lines may yield agents that have therapeutic significance for other diseases in addition to cancer.
The p53 conditional cell lines and their paired control lines are available for exclusive or non-exclusive licensing.
A US patent has issued, and foreign patent applications are pending. (May 30, 2000)