Our overall objective is to study the molecular, cellular and genetic basis for control of cell proliferation in normal human cells. We propose two series of experiments. The first series continues our studies on human fibroblasts. We propose several experiments that will test specific predictions of our hypothesis concerning the molecular basis for finite proliferative lifespan, senescence, quiescence and anchorage dependence. We also propose to investigate the genetic basis for these four phenotypes in order to determine how many genes are involved in determining each phenotype and whether some of these phenotypes have one or more genes in common. The second series of experiments deals with human keratinocytes. We propose to investigate whether keratinocytes exhibit the same kinds of control of cell proliferation as do fibroblasts. This is of particular interest because keratinocytes are quite different from fibroblasts in vivo, i.e., they are epithelial cells, they are a replicating cell type in vivo, and they undergo a readily identifiable process of terminal differentiation. We also propose to compare the mechanism for cessation of proliferation due to senescence, quiescence and terminal differentiation in keratinocytes.
