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Potential molecular mechanism for rodent tumorigenesis: mutational generation of Progression Elevated Gene-3 (PEG-3)

Oncogene volume 24, pages 2247–2255 (2005)Cite this article

Abstract

Progression Elevated Gene-3 (PEG-3) was cloned using subtraction hybridization as an upregulated transcript associated with transformation and tumor progression of rat embryo fibroblast cells. PEG-3 is a unique gene facilitating tumor progression by modulating multiple pathways in transformed cells, including genomic stability, angiogenesis and invasion. PEG-3 originates from mutation in the growth arrest and DNA damage inducible gene GADD34. A one base deletion in rat GADD34 results in a frame-shift and premature appearance of a stop-codon resulting in a C-terminally truncated molecule that is PEG-3. We now document that mutation in the GADD34 gene is a frequent event during transformation and/or immortalization of rodent cells. Sequencing of the GADD34 gene in a number of independent rat tumor cell lines revealed that in a majority of these the GADD34 gene is mutated to either PEG-3 or a PEG-3-like gene with similar C-terminal truncations. An important function of GADD34 is to inhibit cell growth, predominantly by apoptosis, and we demonstrate that PEG-3 or C-terminal truncations of human GADD34 resembling PEG-3 prevent growth inhibition by both human and rat GADD34. Phosphorylation of p53 by GADD34 is one mechanism by which it inhibits growth and PEG-3 could prevent GADD34-induced p53 phosphorylation. In contrast, PEG-3 was unable to block other GADD34-induced changes, including eIF2α dephosphorylation, indicating that its effects on GADD34 may be related more to its effect on cell growth rather than a global inhibitor of all GADD34 functions. We hypothesize that mutational generation of PEG-3 or a similar molecule is a critical event during rodent carcinogenesis. The inherent property of PEG-3 to function as a dominant negative of the growth inhibitory property of GADD34 might rescue cells from DNA damage-induced apoptosis leading to growth independence and tumorigenesis.

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Acknowledgements

The present research was supported in part by National Institutes of Health Grant CA35675, the Samuel Waxman Cancer Research Foundation and the Chernow Endowment. PBF is the Michael and Stella Chernow Urological Cancer Research Scientist in the Departments of Pathology, Urology and Neurosurgery at Columbia University Medical Center and an SWCRF Investigator.

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  1. Zao-zhong Su, Luni Emdad and Devanand Sarkar: These authors contributed equally to this study

Authors and Affiliations

  1. Department of Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, 630 West 168th Street, New York, NY, 10032, USA

    Zao-zhong Su, Luni Emdad, Devanand Sarkar & Paul B Fisher

  2. Department of Radiation Oncology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA, 23298, USA

    Aaron Randolph, Kristofer Valerie, Adly Yacoub & Paul Dent

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  1. Zao-zhong Su
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Correspondence to Paul B Fisher.

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Su, Zz., Emdad, L., Sarkar, D. et al. Potential molecular mechanism for rodent tumorigenesis: mutational generation of Progression Elevated Gene-3 (PEG-3). Oncogene 24, 2247–2255 (2005). https://doi.org/10.1038/sj.onc.1208420

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