Potential molecular mechanism for rodent tumorigenesis: mutational generation of Progression Elevated Gene-3 (PEG-3).
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 eIF2 alpha 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.
Su
Zao-zhong
ZZ
Department of Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, College of Physicians and Surgeons, New York, NY 10032, USA.
Emdad
Luni
L
Sarkar
Devanand
D
Randolph
Aaron
A
Valerie
Kristofer
K
Yacoub
Adly
A
Dent
Paul
P
Fisher
Paul B
PB
D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics* / Q000378:metabolism; D017209:Apoptosis; D018797:Cell Cycle Proteins; D002455:Cell Division; D002471:Cell Transformation, Neoplastic; D004249:DNA Damage; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress; D010766:Phosphorylation; D014176:Protein Biosynthesis; D054645:Protein Phosphatase 1; D011506:Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins; D051381:Rats; D011919:Rats, Inbred Strains; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000943:Antigens, Differentiation; D018797:Cell Cycle Proteins; D009363:Neoplasm Proteins; C489287:Ppp1r15a protein, rat; D011506:Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C087519:PPP1R15A protein, human; D054645:Protein Phosphatase 1