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Signal-dependent protection from apoptosis in mice expressing caspase-resistant Rb

Nature Cell Biology volume 4, pages 757–765 (2002)Cite this article

Abstract

The retinoblastoma tumour suppressor protein RB is cleaved by caspases during apoptosis. Here we have mutated the caspase cleavage site in the carboxy terminus of the murine Rb protein in the mouse germ line to create the Rb-MI allele. After endotoxic shock, expression of Rb-MI inhibits apoptosis in the intestines, but not in the spleen, and promotes the survival of male mice. Fibroblasts expressing Rb-MI protein are protected from apoptosis induced by the tumour-necrosis factor-α type I receptor (TNFRI) but remain sensitive to cell death induced by DNA damage. Correspondingly, the release of cytochrome c and the activation of caspase-3 induced by TNFRI, but not by DNA damage, are defective in cells expressing Rb-MI. Our results highlight the importance of Rb cleavage in TNFRI-induced apoptosis.

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Figure 1: Generation of the Rb-MI allele.
Figure 2: Response of Rb-MI mice to endotoxic shock
Figure 3: Effect of Rb-MI on apoptosis in the developing retina.
Figure 4: Loss of Rb sensitizes fibroblasts to apoptosis induced by TNF-α.
Figure 5: Rb-MI inhibits apoptosis induced by TNFRI.
Figure 6: Signal-dependent inhibition of apoptosis by Rb-MI.

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Acknowledgements

We thank members of the Wang lab for comments; M. Kingsbury for help in statistical analysis; R. Johnson for help with ES cell culture; N. Varki for histological analyses; S. Rossi for quantitative cytokine assays and M. Karin for Tnfr1−/- cells. B.N.C. is supported by a Damon Runyon Cancer Research Foundation Fellowship, H.L.B. is supported by a CAPES fellowship (Brazil), and A.M. is supported by the Ernst Schering Research Foundation (Germany). This work was supported by an NIH grant to J.Y.J.W.

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Author notes

  1. Tung-Ti Chen

    Present address: AmProx Incorporated, 2120 Las Palmas Drive, Suite F, Carlsbad, California, 92009, USA

  2. B. Nelson Chau and Helena Lobo Borges: These authors contributed equally to this work

Authors and Affiliations

  1. Division of Biology and the Cancer Center, 9500 Gilman Drive 0322

    B. Nelson Chau, Helena Lobo Borges, Anja Masselli, Irina C. Hunton & Jean Y. J. Wang

  2. University of California, San Diego, La Jolla, 92093-0322, California, USA

    B. Nelson Chau, Helena Lobo Borges, Anja Masselli, Irina C. Hunton & Jean Y. J. Wang

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Correspondence to Jean Y. J. Wang.

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Chau, B., Borges, H., Chen, TT. et al. Signal-dependent protection from apoptosis in mice expressing caspase-resistant Rb. Nat Cell Biol 4, 757–765 (2002). https://doi.org/10.1038/ncb853

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