Regulation of cell proliferation is likely to be a complex process involving the coordinate expression of discrete genes. Approaches used in identifying the genetic elements involved in controlling cell proliferation have emphasized the initial event the commitment of regulatory events which arrest the proliferation of dividing cells and restores them to the quiescent state. This study takes such an approach by examining changes in gene expression associated with the arrest of proliferation. Employing recombinant DNA cloning and interferon as a growth antagonist, four cDNA sequences have been identified and isolated which appear to correspond to genes (AP) that participate in mediating the antiproliferative action of interferon. These AP genes also appear to be associated with the """"""""natural"""""""" inhibit6ion of proliferation accompanying contact-inhibition. The proposed research is directed towards: (1) characterizing the structural and functional features of the AP genes; (2) obtaining a clearer understanding of how changes in cell shape can exert a regulatory influence on cell proliferation; and (3) determining if AP and similar genes play a role in cellular differentiation. Structural information regarding the AP genes is derived from sequencing the cDNAs as well as their corresponding genomic sequences. Functional characterization concentrates on examining the causal relationship between changes in the expression of the AP genes and changes in the cell's proliferative states. A shape-dependent growth regulatory mechanism has been demonstrated for cells in culture. The possibility that this mechanism operates via the AP genes is examined in cells whose shape is systematically altered by culturing on poly(HEMA). Human neuroblastoma cells, induced to differentiate by retinoic acid; are used to determine if the proliferation arrest which precedes differentiation is mediated by AP or other AP-like genes. Throughout this study special emphasis is placed on extrapolating the expression of AP genes to its possible role as a natural regulator of cell proliferation. Moreover, these studies are expected to help assess whether the arrest of proliferation is an active event associated with the induction of genes whose expression results in proliferation arrest, or a passive event associated with the repression of genes whose continued expression is required for the maintenance of the proliferative state, or a combination of both.
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