¹Department of Pediatrics, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, TN 37232, USA

²Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, TN 37232, USA

Correspondence to: E Yang, 397 PRB, Vanderbilt Medical Center, Nashville, Tennessee, TN 37232, USA. E-mail: elizabeth.yang@vanderbilt.edu

The anti-apoptotic molecules BCL-x_L and BCL2 delay cell cycle entry from quiescence. We used serum induction and induction of a Myc-estrogen receptor fusion protein (MycER) in quiescent fibroblasts to investigate the mechanisms underlying the cell cycle activity of BCL-x_L and BCL2. We demonstrate for the first time that BCL-xL and BCL2 delayed serum-induced and Myc-induced, but not E2F-induced, cell cycle entry. The cyclin-dependent kinase inhibitor p27 was elevated during serum deprivation and cell cycle entry in BCL-x_L or BCL2-expressing NIH3T3 cells and a Rat1MycER cell line. Activation of cyclin-dependent kinase 2 (cdk2) and cyclin-dependent kinase 4 (cdk4) were delayed during progression to S phase, while the induction of cyclin D1 protein, as well as the levels of cyclin E, cdk2, and cdk4 were unaltered by BCL-x_L or BCL2. Inhibition of cyclin/cdk activities in BCL-x_L or BCL2 expressing cells was associated with excess p27 in the cyclin/cdk complexes. Neither BCL-x_L nor BCL2 delayed S phase entry in cells deficient in p27, thus p27 is required for the cell cycle function of BCL-x_L and BCL2. The cell cycle effects of BCL-x_L and BCL2 were more profound in Myc-induced than in serum-induced cell cycle entry. Our results suggest that one possible mechanism by which BCL-x_L and BCL2 delay cell cycle entry may be the inhibition of Myc activity through the elevation of p27.

Oncogene (2002) 21, 7765-7775. doi:10.1038/sj.onc.1205928

BCL2; BCL-x_L; cell cycle; p27; cdk; Myc