Abstract
p27(Kip1) regulates the decision to enter into S-phase or withdraw from the cell cycle by establishing an inhibitory threshold above which G1 cyclin-dependent kinases accumulate before activation. We have used the HL-60 cell line to study regulation of p27 as cells withdraw from the cell cycle following treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA). We found that the amount of p27 is maximal in G0 cells, lower in G1 cells, and undetectable in S-phase cells. In contrast to the protein, the amount of p27 mRNA was the same in these populations, suggesting that accumulation of p27 during the cell cycle and as cells withdraw from the cell cycle is controlled by post-transcriptional mechanisms. In S-phase cells, the degradation of p27 appears to predominate as a regulatory mechanism. In G0 cells, there was an increase in the synthesis rate of p27. Our data demonstrate that, in G0 cells, accumulation of p27 is due to an increase in the amount of p27 mRNA in polyribosomes.
Highlights
The activation status of the cyclin-dependent kinases (CDKs)1 regulates progression through G1 [1]
A class of proteins that interact with both G1 CDKs, called Kips (CDK inhibitory proteins), might coordinate these two classes of kinases and the start of S-phase. p27Kip1 might directly bridge the activation of cyclin E1⁄7CDK2 complexes to expression of cyclin D1⁄7CDK complexes [4, 5]. p21Kip1 might regulate cyclin1⁄7CDK2 complexes at a checkpoint following DNA damage or nucleotide pool perturbation (6 – 8)
Cell Cycle-dependent and Growth-dependent Post-transcriptional Regulation of p27 in HL-60 Cells—The decision to either proliferate or withdraw from the cell cycle is made during G1 phase and is affected by the relative amounts of cyclin1⁄7CDK complexes and CDK inhibitors [18, 21,22,23,24,25]
Summary
The activation status of the cyclin-dependent kinases (CDKs)1 regulates progression through G1 [1]. P27Kip1 regulates the decision to enter into S-phase or withdraw from the cell cycle by establishing an inhibitory threshold above which G1 cyclin-dependent kinases accumulate before activation. In contrast to the protein, the amount of p27 mRNA was the same in these populations, suggesting that accumulation of p27 during the cell cycle and as cells withdraw from the cell cycle is controlled by post-transcriptional mechanisms.
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