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Abstract
We have determined how the phosphorylation of the retinoblastoma family (pRb, p107, and p130) is governed in individual cell cycle phases of Daudi B-cells during cell cycle exit triggered by alpha-interferon (alpha-IFN). alpha-IFN causes dephosphorylation of pRb and loss of p130 phosphorylated Form 3. However, the change in p130 phosphorylation in response to alpha-IFN occurs before dephosphorylation of pRb is complete because loss of p130 Form 3 occurs throughout the cell cycle prior to complete arrest in G1, whereas pRb is dephosphorylated only in G1. In contrast, p107 is dephosphorylated and is then depleted from cells as they exit the cell cycle. p130, predominantly in Form 1, and hypophosphorylated pRb bind an E2F DNA binding site; p130 complexes E2F-4, whereas pRb binds both E2F-4 and E2F-1. The phosphorylated forms of E2F-4 that bind to the E2F DNA site are different from hyperphosphorylated E2F-4, which predominates in primary hemopoietic cells in G0. We conclude that although cell cycle arrest induced by alpha-IFN may be mediated in part by formation of a complex containing p130 and E2F-4, alpha-IFN does not induce hyperphosphorylation of E2F-4, which characterizes primary hemopoietic cells in G0.
Highlights
Cell Cycle Phosphorylation of the pRb FamilyE2F-4 in combination with DP-1 [30, 34] causes quiescent cell lines to progress through G1 into S phase
The protein encoded by the RB gene, pRb, is a nuclear phosphoprotein that is involved in regulating progression through G1 into S phase
Exit from the cell cycle caused by transforming growth factor- results in the accumulation of p130 Form 1, and exit caused by serum starvation results in the accumulation of Form 2 [14]. p107 is not phosphorylated as cells enter G1 from G0 but is phosphorylated from S phase onward [18]
Summary
E2F-4 in combination with DP-1 [30, 34] causes quiescent cell lines to progress through G1 into S phase. PRb, p107, and p130 have been shown to bind individual E2Fs at different stages during entry into the first cell cycle (Ref. 26 and references therein), and so transcription controlled by specific E2Fs could be repressed at different times Such coordinated activation of transcription is required for cell proliferation because transfection of either pRb, p107, or p130 will prevent progression into the cell cycle, which can be overcome by increased expression of individual E2Fs (17, 38 – 40). The processes regulating entry into the cell cycle (G03 G13 S) may be different from those regulating cell cycle progression through G1 in actively cycling cells (M3 G13 S) [67] and are poorly understood This is important because negative growth factors, such as ␣-IFN, exert their effects on actively cycling cells. Our studies show that regulation of the phosphorylation of pRb and p107 is different from that of p130 during the cell cycle of actively proliferating cells and that each is regulated in a different manner by ␣-IFN as cells exit the cell cycle
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