TGF-beta1-mediated hypertrophy involves inhibiting pRB phosphorylation by blocking activation of cyclin E kinase.
When renal epithelial cells are exposed to epidermal growth factor-transforming growth factor-beta1 (EGF-TGF-beta1) the typical EGF-mediated hyperplastic growth response is converted to a hypertrophic growth response. Hypertrophy in this setting involves cell entrance into G(1), but arrest of cell cycle progression at the G(1)/S interface. Late G(1) arrest is mediated by retaining retinoblastoma protein (pRB) in its active, hypophosphorylated state. The present studies examine the mechanism by which pRB is retained in its active state. The results demonstrate that TGF-beta1-mediated conversion of hyperplasia to hypertrophy involves preventing activation of cdk2/cyclin E kinase but has no effect on cdk4(6)/cyclin D kinase activity. Preventing activation of cyclin E kinase is associated with 1) decreased abundance of cdk2/cyclin E complexes and 2) retention of p57(Kip2) in formed cdk2/cyclin E complexes. The development of hypertrophy does not involve regulation of either cdk2, cyclin E, or cdc25A protein abundances, or the abundance of p27(Kip1) or p21 in formed complexes.
Liu
B
B
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75235-8856, USA.
Preisig
P
P
D000818:Animals; D042846:CDC2-CDC28 Kinases; D018797:Cell Cycle Proteins; D002460:Cell Line; D019927:Cyclin E; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D050760:Cyclin-Dependent Kinase Inhibitor p27; D050761:Cyclin-Dependent Kinase Inhibitor p57; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D006984:Hypertrophy; D007668:Kidney / Q000166:cytology / Q000187:drug effects* / Q000473:pathology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D051381:Rats; D016160:Retinoblastoma Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins; D020687:cdc25 Phosphatases
C493962:Cdkn1b protein, rat; D018797:Cell Cycle Proteins; D019927:Cyclin E; D050761:Cyclin-Dependent Kinase Inhibitor p57; D008869:Microtubule-Associated Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004815:Epidermal Growth Factor; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495892:Cdk2 protein, rat; C495903:Cdk4 protein, rat; D051357:Cyclin-Dependent Kinase 2; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; C517007:Cdc25a protein, rat; D017027:Protein Tyrosine Phosphatases; D020687:cdc25 Phosphatases