Prolonged activation of the mitogen-activated protein kinase pathway promotes DNA synthesis in primary hepatocytes from p21Cip-1/WAF1-null mice, but not in hepatocytes from p16INK4a-null mice.

摘要: In primary rat hepatocytes, prolonged activation of the p42/44 mitogen-activated protein kinase (MAPK) pathway is associated with a decrease in DNA synthesis and increased expression cyclin-dependent inhibitor (CKI) proteins p21Cip-1/WAF1 p16INK4a. To evaluate relative importance these CKIs mediating this response, we determined impact MAPK on cultures hepatocytes derived from mice embryonically deleted (null) for either or When was activated wild-type mouse 24 h, via infection construct to express an inducible oestrogen receptor-Raf-1 fusion (DeltaRaf:ER), p16INK4a CKI increased, 2 (cdk2) cdk4 activities decreased, decreased. Inhibition RhoA GTPase function basal p27Kip-1 but not p16INK4a, enhanced ability signalling synthesis. Ablation CCAATT enhancer-binding alpha (C/EBPalpha), C/EBPbeta, decreased induce p21Cip-1/WAF1. p16INK4a-null cdk2 contrast findings, p21Cip-1/WAF1-null caused large increase synthesis, despite elevated activity cells partly blunted both levels Expression anti-sense p21Cip-1/WAF1, permitted These results argue that inhibit requires has smaller role stimulus mediate growth arrest. Our also suggest can modulate p27Kip-1.