The antiproliferative effect of beta-carotene requires p21(waf1/cip1) in normal human fibroblasts

In normal human fibroblasts, beta-carotene induces a cell-cycle delay in th e G1 phase independent of its provitamin A activity via a mechanism not yet elucidated. In this study we provide biochemical evidence showing that del ayed progression through the G1 phase occurs concomitantly with: an increas e in both nuclear-bound and total p21(waf1/cip1) protein levels; an increas e in the amount of p21(waf1/cip1) associated with cdk4; the inhibition of c yclin D1-associated cdk4 kinase activity; and a reduction in the levels of hyperphosphorylated forms of retinoblastoma protein, and particularly, in p hosphorylated Ser780. The role of p21(waf1/cip1) in the antiproliferative e ffect of the carotenoid was further supported by genetic evidence that neit her changes in cell-cycle progression nor in the phosphorylation status of retinoblastoma protein were observed in p21(waf1/cip1)-deficient human fibr oblasts treated with beta-carotene. These results clearly demonstrate that p21(waf1/cip1) is involved directly in the molecular pathway by which beta- carotene inhibits cell-cycle progression.