Title

p37Ing1b regulates B-cell proliferation and cooperates with p53 to suppress diffuse large B-cell lymphomagenesis

UMMS Affiliation

Graduate School of Biomedical Sciences; Department of Cell Biology; Department of Molecular Genetics and Microbiology

Date

11-1-2008

Document Type

Article

Medical Subject Headings

Animals; B-Lymphocytes; Base Sequence; *Cell Proliferation; DNA Primers; Humans; Intracellular Signaling Peptides and Proteins; Lymphoma, Large B-Cell, Diffuse; Mice; Mice, Inbred C57BL; Mice, Knockout; Nuclear Proteins; Reverse Transcriptase Polymerase Chain Reaction; Tumor Suppressor Protein p53; Tumor Suppressor Proteins

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

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.

Rights and Permissions

Citation: Cancer Res. 2008 Nov 1;68(21):8705-14. Link to article on publisher's site

Related Resources

Link to Article in PubMed

PubMed ID

18974112