The anti-apoptosis molecules BCL2 and BCL-xL delay cell cycle entry. The decision of a cell to be in G0 quiescence or to re-enter the cell cycle is important in normal homeostasis and in oncogenesis. The significance of both the anti-apoptosis and anti-proliferative functions of BCL2 has been demonstrated in animal models of tumorigenesis and in human cancers. BCL2 and BCL-xL expression delays the transition from G0 to S by a process requiring the presence of p27. We found that in cells expressing BCL2 and BCLxL, induction of the early G1 genes c-Myc and cyclin D1 were unaffected, but p27 was significantly elevated and activation of G1 cyclin-dependent kinases was inhibited. BCL2 or BCL-xL blocked c-Myc-induced cell cycle progression efficiently, but did not delay cell cycle entry in myc -/- cells. Cell size and RNA content analyses indicated that BCL2 and BCL-xL delayed cell growth that normally accompanies entry into cell cycle from G0, suggesting that cell growth and cell cycle progression were uncoupled. Our data indicate that BCL2 and BCL-xL inhibit G1 progression and delay G0-G1 transition by elevating p27 and inhibiting events downstream of Myc. We hypothesize that BCL2 and BCL-xL regulate cell growth during cell cycle entry by playing a role in mitochondria bioenergetics. We propose to test our hypothesis by 1) elucidating the mechanism of p27 upregulation, 2) identifying the specific cell cycle functions of Myc affected by BCL2 and BCL-xL, and 3) determining the role of BCL2 and BCL-xL in mitochondrial proliferation during emergence from quiescence. The goals of this grant are to elucidate the molecular mechanism of cell cycle delay by BCL2 and BCL-xL and to determine the physiologic significance of regulation of cell cycle entry by BCL2 or BCL-xL.
