Coordinated synthesis and degradation of cdc2 in the mammalian cell cycle

Abstract

The product of the cdc2 gene (cdc2 or p34cdc2), the catalytic subunit of M phase-promoting factor (MPF), is held at a constant steady-state level throughout the cell cycle. In this report, we show that the constant concentration is maintained by a coordinated regulation of protein synthesis and degradation. At the end of each mitosis, cdc2 transcription is shut off, and the mRNA is rapidly degraded. A 12-fold activation of cdc2 gene transcription occurs every round of the cell cycle at the G1/S transition, in a growth factor-dependent manner. The increase in mRNA correlates with the accumulation of newly synthesized cdc2 during S and G2 phases. At the onset of mitosis, the translation of cdc2 mRNA is shut off. During G1 phase, the cdc2 protein has a relatively long half-life of 18 hr, so cdc2 made in the previous cell cycle is maintained. Once synthesis is activated at G1/S, a concurrent mechanism of degradation is activated, and the protein half-life is reduced to 7.5 hr. By the end of interphase, new cdc2 accounts for 75-85% of the total cdc2 pool. In addition, we show that greater than 75% of the new cdc2 complexes with cyclin, suggesting that a majority of the new cdc2 functions as MPF.