Hypo-phosphorylation of the retinoblastoma protein (pRb) by cyclin D:Cdk4/6 complexes results in active pRb.
In cycling cells, the retinoblastoma protein (pRb) is un- and/or hypo-phosphorylated in early G1 and becomes hyper-phosphorylated in late G1. The role of hypo-phosphorylation and identity of the relevant kinase(s) remains unknown. We show here that hypo-phosphorylated pRb associates with E2F in vivo and is therefore active. Increasing the intracellular ... concentration of the Cdk4/6 specific inhibitor p15(INK4b) by transforming growth factor beta treatment of keratinocytes results in G1 arrest and loss of hypo-phosphorylated pRb with an increase in unphosphorylated pRb. Conversely, p15(INK4b)-independent transforming growth factor beta-mediated G1 arrest of hepatocellular carcinoma cells results in loss of Cdk2 kinase activity with continued Cdk6 kinase activity and pRb remains only hypo-phosphorylated. Introduction of the Cdk4/6 inhibitor p16(INK4a) protein into cells by fusion to a protein transduction domain also prevents pRb hypo-phosphorylation with an increase in unphosphorylated pRb. We conclude that cyclin D:Cdk4/6 complexes hypo-phosphorylate pRb in early G1 allowing continued E2F binding.
Mesh Terms:
Carrier Proteins, Cell Cycle Proteins, Cell Line, Cyclin D, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Cyclin-Dependent Kinase Inhibitor p15, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinases, Cyclins, DNA-Binding Proteins, E2F Transcription Factors, G1 Phase, Humans, Phosphorylation, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Retinoblastoma Protein, Retinoblastoma-Binding Protein 1, Signal Transduction, Transcription Factor DP1, Transcription Factors, Transforming Growth Factor beta, Tumor Cells, Cultured, Tumor Suppressor Proteins
Carrier Proteins, Cell Cycle Proteins, Cell Line, Cyclin D, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Cyclin-Dependent Kinase Inhibitor p15, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinases, Cyclins, DNA-Binding Proteins, E2F Transcription Factors, G1 Phase, Humans, Phosphorylation, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Retinoblastoma Protein, Retinoblastoma-Binding Protein 1, Signal Transduction, Transcription Factor DP1, Transcription Factors, Transforming Growth Factor beta, Tumor Cells, Cultured, Tumor Suppressor Proteins
Proc. Natl. Acad. Sci. U.S.A.
Date: Sep. 30, 1997
PubMed ID: 9380698
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