The reduced expression of surrogate light chains in B cell precursors from senescent BALB/c mice is associated with decreased E2A proteins

Sherwood, Erin M.; Xu, Wei; King, Anne M.; Blomberg, Bonnie B.; Riley, Richard L.

doi:10.1016/s0047-6374(00)00157-3

Cited by 55 publications

(106 citation statements)

References 28 publications

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“…Both transcription of the RAG enzymes and the surrogate L chain proteins in B cell precursors are, in part, mediated by the E2A-encoded transcription factors E47 and E12 (10). Previously, we have shown that E2A-encoded protein levels are reduced in B cell precursors from aged mice after their expansion with IL-7 in vitro (9,11,12). This was associated with reduction in the expression of 5 protein and reflected in decreased 5 and VpreB mRNAs (9).…”

mentioning

confidence: 89%

“…Previously, we have shown that E2A-encoded protein levels are reduced in B cell precursors from aged mice after their expansion with IL-7 in vitro (9,11,12). This was associated with reduction in the expression of 5 protein and reflected in decreased 5 and VpreB mRNAs (9). The reduced steady-state levels of E47 proteins seen in cultured aged B cell precursors were demonstrated to result primarily from increased proteasome-mediated protein turnover (12).…”

mentioning

confidence: 90%

“…Densitometry values for desired proteins were normalized to that of the loading controls. In some experiments, normalized values of experimental proteins in old lysates (e.g., E47) were expressed relative to young controls (9,12).…”

Section: Immunoprecipitation and Western Blot Analysismentioning

confidence: 99%

“…The decline in B lymphopoiesis in senescent mice coincides with reduced expression of RAG-2 and capacity to rearrange genes at the V H loci (5-7). Furthermore, diminished expression of the surrogate L chain components 5 and VpreB in aged B cell precursors suggests that signaling may be compromised at the pre-BCR checkpoint (3,8,9). Both transcription of the RAG enzymes and the surrogate L chain proteins in B cell precursors are, in part, mediated by the E2A-encoded transcription factors E47 and E12 (10).…”

mentioning

confidence: 99%

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Accelerated Notch-Dependent Degradation of E47 Proteins in Aged B Cell Precursors Is Associated with Increased ERK MAPK Activation

King

Put

Blomberg

et al. 2007

The Journal of Immunology

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The transcriptional regulator E47, encoded by the E2A gene, is crucial to B lymphopoiesis. In BALB/c senescent mice (∼2 years old), the incidence of E47-expressing pro-B cells in vivo and E47 protein steady state levels in B cell precursors in vitro were reduced. Poor expression of E47 protein was a consequence of accelerated proteasome-mediated turnover and was associated with heightened ubiquitin modification of E2A-encoded proteins in aged B cell precursors. Both MAPK and Notch activity have been previously associated with E2A-encoded protein stability in lymphocytes. Aged B cell precursors exhibited heightened levels of MAPK activity reflected in increased levels of phospho-ERK proteins. Phosphorylation of E2A-encoded proteins was also increased in aged B cell precursors and pharmacologic inhibition of MEK-1 resulted in a partial restoration of their E47 protein. Both Notch proteins and their Delta-like ligands were detected comparably in young and aged B cell precursors. Either inhibition of Notch activation via gamma-secretase or Ab blockade of Notch-Delta-like ligand interactions partially restored E47 expression in aged B cell precursors. We hypothesize that increased MAPK activity promotes phosphorylation of E2A-encoded protein in aged B cell precursors. Subsequently, E2A-encoded proteins undergo ubiquitination and accelerated degradation in a Notch-dependent process. The dysregulation of E2A-encoded protein expression may contribute to the reductions seen in early B lymphopoiesis during murine senescence.

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mentioning

confidence: 89%

mentioning

confidence: 90%

Section: Immunoprecipitation and Western Blot Analysismentioning

confidence: 99%

mentioning

confidence: 99%

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Accelerated Notch-Dependent Degradation of E47 Proteins in Aged B Cell Precursors Is Associated with Increased ERK MAPK Activation

King

Put

Blomberg

et al. 2007

The Journal of Immunology

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“…Age related changes in bone marrow B cell commitment and development include declines in the frequency of precursors, lowered expression of key genes, reductions in pro-and pre-B cell compartments, and attenuated responsiveness to differentiation factors (Frasca, Nguyen et al 2004;Labrie, Sah et al 2004;Miller, Izon et al 2002;Riley, Kruger et al 1991;Sherwood, Xu et al 2000;Stephan, Reilly et al 1998;Stephan, Sanders et al 1996;Szabo, Shen et al 2003). Overall, these findings suggest reductions in the generation and throughput of B cell progenitors.…”

Section: B Lineage Progenitors Decline With Age Suggesting New Homeomentioning

confidence: 99%

B cells and aging: Balancing the homeostatic equation

Miller

Cancro

2007

Experimental Gerontology

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The interplay of selective and homeostatic processes dominates the behavior of B lineage subsets following B cell antigen receptor (BCR) expression, and extends to determinants of immune response quality and the persistence of immunologic memory. A key concept emerging from these considerations is that primary events acting upstream of mature B lymphocyte pools can profoundly impact downstream populations as the system attempts homeostatic adjustments. Since advancing age is accompanied by profound changes in B cell generation and homeostasis, establishing the relative contributions of primary lesions versus compensatory homeostatic processes is critical to understanding these perturbations. Exploration of this problem requires an understanding of: 1) the identity, dynamics, and progenitor/successor relationships of marrow and peripheral B cell subsets; 2) the nature and interactions of selective and homeostatic processes acting in these subsets; and 3) how these change with age. Our data show that BLyS and its receptors mediate peripheral B cell homeostasis, and that the size, dynamics and behavior of all B cell subsets influenced by B Lymphocyte Stimulator change with age. These findings suggest that homeostatic processes mediated through B Lymphocyte Stimulator are altered with age, and that these perturbations may primarily reflect compensatory homeostatic adjustments to upstream reductions in B cell generation.

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Aged mice exhibit distinct peripheral B‐cell phenotypes differing in apoptotic susceptibility: An ex vivo analysis

Verdier¹,

Malissein²,

E³

et al. 2006

Cytometry Pt A

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Background: Age-related changes in the antibody response have been classically associated with alterations in T-cell help, but increasing evidence shows that intrinsic B-cell defects exist. This article analyzes the apoptotic susceptibility of peripheral B-cells in aged and young control mice. Materials and Methods: Freshly isolated lymphocytes from spleen and Peyer's patches (PPs) were labeled for Bcell lineage (B220 1 cells) and germinal center B subset (GCs, B2201 /PNA 1 cells). Alternatively, splenic B-cells purified by MACS were used. Apoptosis was monitored by the Annexin V binding, incorporation of 3,3 0 -dihexyloxacarbocyanine iodide (DiOC 6 (3)), propidium iodide (PI) staining, and morphological changes. Moreover, intracellular Bcl-2 expression and Bad phosphorylation status were also analyzed in B-cells. Results: We showed in aging mice an enhanced Annexin V

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The reduced expression of surrogate light chains in B cell precursors from senescent BALB/c mice is associated with decreased E2A proteins

Cited by 55 publications

References 28 publications

Accelerated Notch-Dependent Degradation of E47 Proteins in Aged B Cell Precursors Is Associated with Increased ERK MAPK Activation

Accelerated Notch-Dependent Degradation of E47 Proteins in Aged B Cell Precursors Is Associated with Increased ERK MAPK Activation

B cells and aging: Balancing the homeostatic equation

Aged mice exhibit distinct peripheral B‐cell phenotypes differing in apoptotic susceptibility: An ex vivo analysis

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