Phospholipase D in cellular senescence

Cellular senescence appears to be an important part of organismal aging. Ce llular senescence is characterized by flattened enlarged morphology, inhibi tion of DNA replication in response to growth factors, inability to phospho rylate the pRb tumor suppressor protein, inability to produce c-fos or AP-1 and overexpression of a variety of genes, notably p21 (CIP-1/WAF-1) and p1 6(INK). It is now clear that certain early mitotic signals become defective with the onset of senescence. Among these is the PLD/PKC pathway. Evidence suggests that activation of PLD and PKC is critical for mitogenesis. Recen t data suggest that the defect in PLD/PKC in cellular senescence is a resul t of elevated cellular ceramide levels which inhibit PLD activation. It app ears that the elevated ceramide is a result of neutral sphingomyelinase act ivation. Ceramide acts to inhibit the activation of PLD by possibly three m echanisms, inhibiting activation by Rho, translocation to the membrane and gene expression. Addition of ceramide to young cells not only inhibits PLD but also recapitulates all the standard measures of cellular senescence as described above. (C) 1999 Elsevier Science B.V. All rights reserved.