p37Ing1b regulates B-cell proliferation and cooperates with p53 to suppress diffuse large B-cell lymphomagenesis.
The Inhibitor of Growth (ING) gene family encodes structurally related proteins that alter chromatin to regulate gene expression and cell growth. The initial member, ING1, has also been proposed to function as a tumor suppressor in human cancer based on its ability to suppress cell growth and transformation in vitro. Mouse Ing1 produces two proteins (p31 and p37) from differentially spliced transcripts. We have recently generated p37(Ing1b)-null mice and observed spontaneous follicular B-cell lymphomagenesis in this model to show that ING proteins can function in vivo as tumor suppressors. In this present report, we examine the role of p37(Ing1b) in the regulation of B-cell growth and explore the relationship between p37(Ing1b) and p53-mediated tumor suppression. Our results indicate that p37(Ing1b) inhibits the proliferation of B cells and follicular B cells regardless of p53 status, and loss of p53 greatly accelerates the rate of B-cell lymphomagenesis in p37(Ing1b)-null mice. However, in contrast to the highly penetrant follicular B-cell lymphomas observed in p37(Ing1b)-null mice, mice lacking both p37(Ing1b) and p53 typically present with aggressive diffuse large B-cell lymphomas (DLBL). Analysis of marker gene expression in p37(Ing1b)/p53 null tumors indicates that the double-null mice develop both nongerminal center and germinal center B-cell-like DLBL, and also documents up-regulation of nuclear factor-kappaB activity in p37(Ing1b)/p53-null B cells and B-cell tumors. These results confirm that p53 mutation is an important mechanistic step in the formation of diffuse large B-cell lymphomas and reveals a p53-independent role for Ing1b in suppressing B-cell tumorigenesis.
Coles
Andrew H
AH
Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
Marfella
Concetta G A
CG
Imbalzano
Anthony N
AN
Steinman
Heather A
HA
Garlick
David S
DS
Gerstein
Rachel M
RM
Jones
Stephen N
SN
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D001483:Base Sequence; D049109:Cell Proliferation; D017931:DNA Primers; D006801:Humans; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*
D017931:DNA Primers; C501503:ING1 protein, human; D000076023:Inhibitor of Growth Protein 1; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins