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Regulation of PML-dependent transcriptional repression by pRB and low penetrance pRB mutants

Oncogene volume 21, pages 5557–5565 (2002)Cite this article

Abstract

The retinoblastoma protein (pRB) is thought to suppress tumorigenesis, in part, through interactions with E2F transcription factors. However, certain low penetrance pRB mutants substantially reduce tumor incidence despite having a minimal ability to bind E2F. These low penetrance mutants retain the ability to induce a senescence-like state, suggesting that they may suppress tumorigenesis through a senescence-associated process. Here, we identify a novel pRB function that is associated with senescence and which is retained by non-E2F binding low penetrance pRB mutants. It was found that pRB and these mutants substantially increased the production of PML nuclear bodies (NBs). In keeping with the role of PML in transcriptional repression, pRB also promoted PML-dependent transcriptional repression by the c-Myc antagonist Mad1. In a series of pRB-p130 chimeric proteins, the ability to increase NB production correlated with the ability to induce a senescence-like phenotype. However, neither NB formation nor PML function were required for pRB to induce the senescence-like response. Together, these observations indicate that a pRB-induced increase in PML NB formation is coordinated with, but separable from, the pRB-induced senescence program. The data further suggest that PML may contribute to an E2F-independent tumor suppressor function of pRB.

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Acknowledgements

We thank P Chambon, K-S Chang, M Eilers, F Kaye, P Whyte and L Zhu for plasmid DNAs. We also thank R Weinberg and L Zhu for critical reading of the manuscript, and D Li for technical assistance. This work was supported by grants from the James S McDonnell Foundation, the Dorothy Rodbell Cohen Foundation, and the Human Frontiers Science Program Organization to D Cobrinik and by NIH grant P30CA13696 for support of the Optical Microscopy Facility of the Herbet Irving Comprehensive Cancer Center. T Mori was supported by the Uehara Memorial Foundation and the International Society for Diseases of the Esophagus.

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  1. Takahiro Mori

    Present address: Division of Surgical Oncology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, 980-8574, Sendai, Japan

Authors and Affiliations

  1. Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, 10032, NY, USA

    Weizhao Fang, Takahiro Mori & David Cobrinik

  2. Institute of Cancer Genetics, and Department of Pathology, College of Physicians and Surgeons of Columbia University, New York, 10032, NY, USA

    David Cobrinik

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  1. Weizhao Fang
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Correspondence to David Cobrinik.

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Fang, W., Mori, T. & Cobrinik, D. Regulation of PML-dependent transcriptional repression by pRB and low penetrance pRB mutants. Oncogene 21, 5557–5565 (2002). https://doi.org/10.1038/sj.onc.1205666

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