Polyamine Analogue Induction of the p53-p21WAF1/CIP1-Rb Pathway and G1 Arrest in Human Melanoma Cells

摘要: Although polyamines are well recognized for their critical involvement in cell growth, the cycle specificity of this requirement has not yet been characterized with respect to newly delineated regulatory pathways. We recently reported that polyamine analogues having close structural and functional similarities natural produce a distinct G1 G2-M arrest MALME-3M human melanoma cells. To determine molecular basis observation, we examined effects N 1, 11-diethylnorspermine on proteins associated arrest. The analogue is known deplete pools by suppressing biosynthetic enzymes potently inducing catabolic enzyme spermidine/spermine 1-acetyltransferase. Treatment cells 10 μm caused an increase hypophosphorylated Rb, which correlated temporally onset at 16–24 h. Rb hypophosphorylation was preceded wild-type p53 (∼10-fold maximum) concomitant cyclin-dependent kinase inhibitor, p21WAF1/CIP1 (p21; ∼5-fold maximum). Another p27KIP1, cyclin D1 increased slightly, whereas proliferating nuclear antigen p130 remained unchanged. Induction p21 protein accompanied mRNA, induction not, suggesting transcriptional activation former posttranscriptional regulation latter. SK-MEL-28 cells, contain mutated p53, failed induce or did G1. Rather, these rapidly underwent programmed death within 48 Overall, findings provide first indication pathways antagonists such as might inhibit growth containing further suggest mechanistic differential cellular responses agents.