The antiproliferative effect of beta-carotene requires p21waf1/cip1 in normal human fibroblasts.
In normal human fibroblasts, beta-carotene induces a cell-cycle delay in the G1 phase independent of its provitamin A activity via a mechanism not yet elucidated. In this study we provide biochemical evidence showing that delayed progression through the G1 phase occurs concomitantly with: an increase in both nuclear-bound and total p21waf1/cip1 protein levels; an increase in the amount of p21waf1/cip1 associated with cdk4; the inhibition of cyclin D1-associated cdk4 kinase activity; and a reduction in the levels of hyperphosphorylated forms of retinoblastoma protein, and particularly, in phosphorylated Ser780. The role of p21waf1/cip1 in the antiproliferative effect of the carotenoid was further supported by genetic evidence that neither changes in cell-cycle progression nor in the phosphorylation status of retinoblastoma protein were observed in p21waf1/cip1-deficient human fibroblasts treated with beta-carotene. These results clearly demonstrate that p21waf1/cip1 is involved directly in the molecular pathway by which beta-carotene inhibits cell-cycle progression.
Stivala
L A
LA
Istituto di Patologia generale 'C. Golgi', Università di Pavia, Italy. l.stivala@botta.unipv.it
Savio
M
M
Quarta
S
S
Scotti
C
C
Cazzalini
O
O
Rossi
L
L
Scovassi
I A
IA
Pizzala
R
R
Melli
R
R
Bianchi
L
L
Vannini
V
V
Prosperi
E
E
D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D051358:Cyclin-Dependent Kinase 4; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism*; D005347:Fibroblasts; D005455:Fluorescent Antibody Technique; D016193:G1 Phase / Q000187:drug effects; D006801:Humans; D008081:Liposomes / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D011494:Protein Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein / Q000378:metabolism; D019207:beta Carotene / Q000494:pharmacology*
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D008081:Liposomes; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D019207:beta Carotene; D011494:Protein Kinases; C102333:histone H1 kinase; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases