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Fanconi anemia group C protein prevents apoptosis in hematopoietic cells through redox regulation of GSTP1

Nature Medicine volume 7, pages 814–820 (2001)Cite this article

Abstract

The Fanconi anemia group C protein (FANCC) plays an important role in hematopoiesis by ensuring the survival of hematopoietic progenitor cells through an unknown mechanism. We investigated the function of FANCC by identifying FANCC-binding proteins in hematopoietic cells. Here we show that glutathione S-transferase P1-1 (GSTP1) interacts with FANCC, and that overexpression of both proteins in a myeloid progenitor cell line prevents apoptosis following factor deprivation. FANCC increases GSTP1 activity after the induction of apoptosis. GSTP1 is an enzyme that catalyzes the detoxification of xenobiotics and by-products of oxidative stress, and it is frequently upregulated in neoplastic cells. Although FANCC lacks homology with conventional disulfide reductases, it functions by preventing the formation of inactivating disulfide bonds within GSTP1 during apoptosis. The prevention of protein oxidation by FANCC reveals a novel mechanism of enzyme regulation during apoptosis and has implications for the treatment of degenerative diseases with thiol reducing agents.

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Figure 1: Identification of Gstp1 as a Fancc-interacting protein.
Figure 2: Co-expression of GSTP1 and FANCC promotes increased survival and suppression of apoptosis.
Figure 3: Co-expression of FANCC and GSTP1 in 32D cells stabilizes both proteins following IL-3 withdrawal.
Figure 4: FANCC suppresses apoptosis even in the absence of GSH in 32D cells.
Figure 5: FANCC prevents oxidation of GSTP1 during apoptosis in the absence of GSH.

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Acknowledgements

We thank J. Liu for providing the FANCC retroviral vector, G. Boulianne for comments on the manuscript and D. Riddick for technical advice. This research was supported by the Canadian Institutes of Health Research, the National Institutes of Health (HL52138) and the Burroughs Wellcome Clinical Scientist Award (to H.Y.).

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Authors and Affiliations

  1. Program in Genetics and Genomic Biology, The Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada

    Robert C. Cumming, Jeff Lightfoot & Manuel Buchwald

  2. Graduate Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada

    Robert C. Cumming & Manuel Buchwald

  3. Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada

    Kristin Beard & Peter J. O'Brien

  4. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA

    Hagop Youssoufian

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  1. Robert C. Cumming
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Correspondence to Manuel Buchwald.

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Cumming, R., Lightfoot, J., Beard, K. et al. Fanconi anemia group C protein prevents apoptosis in hematopoietic cells through redox regulation of GSTP1. Nat Med 7, 814–820 (2001). https://doi.org/10.1038/89937

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