Gene expression patterns define novel roles for E47 in cell cycle progression, cytokine-mediated signaling, and T lineage development

doi:10.1073/pnas.0603728103

Gene expression patterns define novel roles for E47 in cell cycle progression, cytokine-mediated signaling, and T lineage development

*Division of Biological Sciences, University of California at San Diego, La Jolla, CA 92093-0377; and
^§Scripps/Florida Research Institute, 5353 Parkside Drive, RF-1, Jupiter, FL 33458

Communicated by Michael S. Levine, University of California, Berkeley, CA, May 5, 2006 (received for review April 7, 2006)

Abstract

In maturing T lineage cells, the helix–loop–helix protein E47 has been shown to enforce a critical proliferation and developmental checkpoint commonly referred to as β selection. To examine how E47 regulates cellular expansion and developmental progression, we have used an E2A-deficient lymphoma cell line and DNA microarray analysis to identify immediate E47 target genes. Hierarchical cluster analysis of gene expression patterns revealed that E47 coordinately regulates the expression of genes involved in cell survival, cell cycle progression, lipid metabolism, stress response, and lymphoid maturation. These include Plcγ2, Cdk6, CD25, Tox, Gadd45a, Gadd45b, Gfi1, Gfi1b, Socs1, Socs3, Id2, Eto2, and Xbp1. We propose a regulatory network linking Janus kinase (JAK)/signal transducer and activator of transcription (STAT)-mediated signaling, E47, and suppressor of cytokine signaling (SOCS) proteins in a common pathway. Finally, we suggest that the aberrant activation of Cdk6 in E47-deficient T lineage cells contributes to the development of lymphoid malignancy.

Footnotes

^¶To whom correspondence should be addressed. E-mail: murre{at}biomail.ucsd.edu
↵ ^†R.S. and I.E. contributed equally to this work.
↵ ^‡Present address: Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, 10355 Science Center Drive, San Diego, CA 92122.
Author contributions: R.S., I.E., and C.M. designed research; R.S., I.E., and M.F.-S. performed research; R.S., I.E., M.F.-S., H.T.P., and C.M. analyzed data; and C.M. wrote the paper.
Conflict of interest statement: No conflicts declared.
Abbreviations:

Abbreviations:

DP,

double positive;

DN,

double negative;

HLH,

helix–loop–helix;

Cdk6,

cyclin-dependent kinase 6;

TCR,

T cell receptor;

NKT,

natural killer T;

T-ALL,

T-acute lymphoblastoid leukemia.