Deletion of p37Ing1 in mice reveals a p53-independent role for Ing1 in the suppression of cell proliferation, apoptosis, and tumorigenesis.
ING proteins have been proposed to alter chromatin structure and gene transcription to regulate numerous aspects of cell physiology, including cell growth, senescence, stress response, apoptosis, and transformation. ING1, the founding member of the inhibitor of growth family, encodes p37(Ing1), a plant homeodomain (PHD) protein that interacts with the p53 tumor suppressor protein and seems to be a critical cofactor in p53-mediated regulation of cell growth and apoptosis. In this study, we have generated and analyzed p37(Ing1)-deficient mice and primary cells to further explore the role of Ing1 in the regulation of cell growth and p53 activity. The results show that endogenous levels of p37(Ing1) inhibit the proliferation of p53-wild-type and p53-deficient fibroblasts, and that p53 functions are unperturbed in p37(Ing1)-deficient cells. In addition, loss of p37(Ing1) induces Bax expression and increases DNA damage-induced apoptosis in primary cells and mice irrespective of p53 status. Finally, p37(Ing1) suppresses the formation of spontaneous follicular B-cell lymphomas in mice. These results indicate that p53 does not require p37(Ing1) to negatively regulate cell growth and offers genetic proof that Ing1 suppresses cell growth and tumorigenesis. Furthermore, these data reveal that p37(Ing1) can negatively regulate cell growth and apoptosis in a p53-independent manner.
Coles
Andrew H
AH
Department of Cell Biology, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA.
Liang
Huiling
H
Zhu
Zhiqing
Z
Marfella
Concetta G A
CG
Kang
Joonsoo
J
Imbalzano
Anthony N
AN
Jones
Stephen N
SN
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D016922:Cellular Senescence / Q000235:genetics; D004249:DNA Damage; D004622:Embryo, Mammalian; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics* / Q000502:physiology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000502:physiology*
C501505:Ing1 protein, mouse; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2