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Distinct roles of the co-activators p300 and CBP in retinoic-acid-induced F9-cell differentiation

Nature volume 393, pages 284–289 (1998)Cite this article

Abstract

The related proteins p300 and CBP (cAMP-response-element-binding protein (CREB)-binding protein)) are transcriptional co-activators that act with other factors to regulate gene expression1,2,3,4,5 and play roles in many cell-differentiation and signal transduction pathways6,7,8,9,10. Both proteins have intrinsic histone-acetyltransferase activity11,12 and may act directly on chromatin, of which histone is a component, to facilitate transcription. They are also involved in growth control pathways, as shown by their interaction with the tumour suppressor p53 (13–15) and the viral oncogenes E1A (refs 1, 2, 16) and SV40 T antigen5. Here we report functional differences of p300 and CBP in vivo. We examined their roles during retinoic-acid-induced differentiation, cell-cycle exit and programmed cell death (apoptosis) of embryonal carcinoma F9 cells17,18,19,20, using hammerhead ribozymes capable of cleaving either p300 or CBP messenger RNAs. F9 cells expressing a p300-specific ribozyme became resistant to retinoic-acid-induced differentiation, whereas cells expressing a CBP-specific ribozyme were unaffected. Similarly, retinoic-acid-induced transcriptional upregulation of the cell-cycle inhibitor p21Cip1 required normal levels of p300, but not CBP, whereas the reverse was true for p27Kip1. In contrast, both ribozymes blocked retinoic-acid-induced apoptosis, indicating that both co-activators are required for this process. Thus, despite their similarities, p300 and CBP have distinct functions during retinoic-acid-induced differentiation of F9 cells.

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Figure 1: Ribozymes specific for p300 or CBP.
Figure 2: Effects of p300- and CBP-directed ribozymes on F9-cell differentiation and RA-dependent transcription.
Figure 3: Apoptosis is inhibited in cells containing a p300- or a CBP-directed ribozyme.
Figure 4: Impact of decreasing p300 or CBP protein levels on cell proliferation.

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Acknowledgements

We thank G. H. Goodman, K. Umezono, B. Vogelstein and T. Sakai for gifts of the pCMV-CBP, RAREβ-luc, p21-luc and p27-luc plasmids, respectively; and K. Itakura and G. Gachelin for discussion. T-P.Y. was supported by the Damon Runyon Walter Winchill Cancer Research Fund. This work was supported by a START grant from the Swiss National Science Foundation (to R.E.), the Life Science Research Project of RIKEN, the Special Cooperation Funds of the Science and Technology Agency, and Grants-in-Aid from the Minsitry of Education, Science and Culture (Japan) (to K.K.Y.).

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Authors and Affiliations

  1. Tsukuba Life Science Center, The Institute of Physical and Chemical Research (RIKEN), 3-1-1 Koyadai, Tsukuba Science City, 305-0074, Japan

    Hiroaki Kawasaki & Kazunari K. Yokoyama

  2. Institute of Applied Biochemistry, University of Tsukuba, Tennoudai 1-1-1, Tsukuba Science City, 305-0006, Japan

    Hiroaki Kawasaki & Kazunari Taira

  3. Institute for Molecular Biology, University of Zürich, CH-8057, Zürich, Switzerland

    Richard Eckner

  4. Dana-Farber Cancer Institute and Harvard Medical School, Boston, 02115, Massachusetts, USA

    Tso-Pang Yao & David M. Livingston

  5. Department of Surgery/Oncology, UCLA School of Medicine and Jonsson Comprehensive Cancer Centre, Los Angeles, 90024, California, USA

    Robert Chiu

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Correspondence to Kazunari K. Yokoyama.

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Kawasaki, H., Eckner, R., Yao, TP. et al. Distinct roles of the co-activators p300 and CBP in retinoic-acid-induced F9-cell differentiation. Nature 393, 284–289 (1998). https://doi.org/10.1038/30538

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