MOLECULAR ASPECTS OF THE RELATIONSHIP BETWEEN CANCER AND AGING - TUMOR-SUPPRESSOR ACTIVITY DURING CELLULAR SENESCENCE

Normal cells cultured in vitro lose their proliferative potential afte r a finite number of doublings in a process termed replicative cellula r senescence (Hayflick, 1965). The roles that growth inhibitory tumor suppressors play in the establishment and maintainence of cellular sen escence have been reported in many different systems. The Rb and p53 t umor suppressors are examples of growth inhibitors that lose the abili ty to be regulated and are constantly activated during senescence. Oth er proteins that inhibit the initiation of DNA synthesis in early pass age fibroblasts and that link the action of tumor suppressors with the cell cycle machinery, are also expressed at higher levels in senescen t cells. For example, the increased expression of the cyclin-dependent kinase inhibitor p16 may contribute to arresting the growth of senesc ent cells. Identification and characterization of additional genes enc oding growth inhibitors that are upregulated in senescent cells, such as the recently isolated p33(ING1) protein, should provide a better un derstanding of the ''aging program'' that ceases to operate in the gen eration of immortal cancer cells. (C) 1998 Elsevier Science Inc.