Decreased E47 in senescent B cell precursors is stage specific and regulated posttranslationally by protein turnover

Elaine Van der Put, Daniela Frasca, Anne M. King, Bonnie B Blomberg, Richard L Riley

Research output: Contribution to journalArticle

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Abstract

The E2A-encoded transcription factor E47 is crucial to B lymphopoiesis. Senescent BALB/c mice (∼2 years old) had reduced pre-B cells ex vivo. Pro-B/early pre-B cells from these aged mice, both ex vivo and in vitro, were deficient in E47 protein. In vitro, IL-7 expanded pro-B/early pre-B cells from young BALB/c mice expressed E47 protein that was relatively stable over a 5-h period. Cultured senescent pro-B/early pre-B cells exhibited reduced E47 protein stability with ∼50-90% loss of E47 over the same time period. Degradation of E47 was effectively blocked by the proteasome inhibitor lactacystin as well as calpain I and II inhibitors; E2A proteins were also shown to undergo ubiquitination. Although senescent B cell precursors expressed less E47 protein, E47 mRNA levels and turnover were normal. Therefore, E47 protein levels are reduced relatively early in B lineage differentiation in senescence and the decline in E47 protein occurs via increased protein degradation by proteasome and, possibly, calpain pathways. In contrast, normal E47 protein levels were observed within the highly reduced pre-B cell pool in aged mice. This suggests that pre-B cells in senescence undergo selection based on E47 expression. Increased degradation rates and lower steady-state levels were also observed for the transcription factors Pax-5/BSAP, Bob-1, and Ikaros, but this was not a general property of all proteins in aged B cell precursors. Therefore, altered turnover of multiple, select proteins crucial to B cell development may contribute to diminished B lymphopoiesis in old age.

Original languageEnglish
Pages (from-to)818-827
Number of pages10
JournalJournal of Immunology
Volume173
Issue number2
StatePublished - Jul 15 2004

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B-Lymphoid Precursor Cells
Proteins
Calpain
Lymphopoiesis
Paired Box Transcription Factors
Interleukin-7
Protein Stability
Cell Aging
Ubiquitination
Proteasome Endopeptidase Complex
Proteolysis
B-Lymphocytes
Transcription Factors
Messenger RNA

ASJC Scopus subject areas

  • Immunology

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Decreased E47 in senescent B cell precursors is stage specific and regulated posttranslationally by protein turnover. / Van der Put, Elaine; Frasca, Daniela; King, Anne M.; Blomberg, Bonnie B; Riley, Richard L.

In: Journal of Immunology, Vol. 173, No. 2, 15.07.2004, p. 818-827.

Research output: Contribution to journalArticle

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abstract = "The E2A-encoded transcription factor E47 is crucial to B lymphopoiesis. Senescent BALB/c mice (∼2 years old) had reduced pre-B cells ex vivo. Pro-B/early pre-B cells from these aged mice, both ex vivo and in vitro, were deficient in E47 protein. In vitro, IL-7 expanded pro-B/early pre-B cells from young BALB/c mice expressed E47 protein that was relatively stable over a 5-h period. Cultured senescent pro-B/early pre-B cells exhibited reduced E47 protein stability with ∼50-90{\%} loss of E47 over the same time period. Degradation of E47 was effectively blocked by the proteasome inhibitor lactacystin as well as calpain I and II inhibitors; E2A proteins were also shown to undergo ubiquitination. Although senescent B cell precursors expressed less E47 protein, E47 mRNA levels and turnover were normal. Therefore, E47 protein levels are reduced relatively early in B lineage differentiation in senescence and the decline in E47 protein occurs via increased protein degradation by proteasome and, possibly, calpain pathways. In contrast, normal E47 protein levels were observed within the highly reduced pre-B cell pool in aged mice. This suggests that pre-B cells in senescence undergo selection based on E47 expression. Increased degradation rates and lower steady-state levels were also observed for the transcription factors Pax-5/BSAP, Bob-1, and Ikaros, but this was not a general property of all proteins in aged B cell precursors. Therefore, altered turnover of multiple, select proteins crucial to B cell development may contribute to diminished B lymphopoiesis in old age.",
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