Effects of depletion of CREB-binding protein on c-Myc regulation and cell cycle G1-S transition

Hasan N. Rajabi, Sudhakar Baluchamy, Sivanagarani Kolli, Alo Nag, Rampalli Srinivas, Pradip Raychaudhuri, Bayar Thimmapaya*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

We recently reported that the transcriptional coactivator and histone acetyltransferase p300 plays an important role in the G1 phase of the cell cycle by negatively regulating c-myc and thereby preventing premature G1 exit (Kolli, et al. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 4646-4651; Baluchamy, et al. (2003) Proc. Natl. Acad. Sci. U. S. A. 100, 9524-9529). Because p300 does not substitute for all CREB-binding protein (CBP) functions, we investigated whether CBP also negatively regulates c-myc and prevents premature DNA synthesis. Here, we show that antisense-mediated depletion of CBP in serum-deprived human cells leads to induction of c-myc and that such cells emerge from quiescence without growth factors at a rate comparable with that of p300-depleted cells. The CBP-depleted cells contained significantly reduced levels of the cyclin-dependent kinase inhibitor p21 and low levels of p107 and p130 (but not pRb) phosphorylation, suggesting that these factors, along with elevated levels of c-Myc, contribute to induction of DNA synthesis. Antisense c-Myc reversed the phosphorylation of p107 and p130 and the induction of S phase in CBP-depleted cells, indicating that up-regulation of c-myc is directly responsible for the induction of S phase. Furthermore, the serum-stimulated p300/CBP-depleted cells did not traverse beyond S phase, and a significant number of these cells died of apoptosis, which was not related to p53 levels. These cells also contained significantly higher levels of c-Myc compared with normal cells. When c-myc expression was blocked by antisense c-Myc, the apoptosis of the serum-stimulated CBP-depleted cells was reversed, indicating that high levels of c-Myc contribute to apoptosis. Thus, despite their high degree of structural and functional similarities, normal levels of both p300 and CBP are essential for keeping c-myc in a repressed state in G 1 and thereby preventing inappropriate entry of cells into S phase. In addition, both these proteins also provide important functions in coordinated cell cycle progression.

Original languageEnglish (US)
Pages (from-to)361-374
Number of pages14
JournalJournal of Biological Chemistry
Volume280
Issue number1
DOIs
StatePublished - Jan 7 2005

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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