King Anne M, Van der Put Elaine, Blomberg Bonnie B, Riley Richard L
Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL 33101, USA.
J Immunol. 2007 Mar 15;178(6):3521-9. doi: 10.4049/jimmunol.178.6.3521.
The transcriptional regulator E47, encoded by the E2A gene, is crucial to B lymphopoiesis. In BALB/c senescent mice (approximately 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.
由E2A基因编码的转录调节因子E47对B淋巴细胞生成至关重要。在BALB/c衰老小鼠（约2岁）中，体内表达E47的前B细胞的发生率以及体外B细胞前体中E47蛋白的稳态水平均降低。E47蛋白表达不佳是蛋白酶体介导的周转加速的结果，并且与衰老B细胞前体中E2A编码蛋白的泛素修饰增加有关。MAPK和Notch活性此前均与淋巴细胞中E2A编码蛋白的稳定性有关。衰老B细胞前体表现出升高的MAPK活性水平，这反映在磷酸化ERK蛋白水平的增加上。衰老B细胞前体中E2A编码蛋白的磷酸化也增加，并且对MEK-1的药理抑制导致其E47蛋白部分恢复。在年轻和衰老的B细胞前体中检测到的Notch蛋白及其Delta样配体相当。通过γ-分泌酶抑制Notch激活或用抗体阻断Notch-Delta样配体相互作用均可部分恢复衰老B细胞前体中的E47表达。我们假设，MAPK活性增加会促进衰老B细胞前体中E2A编码蛋白的磷酸化。随后，E2A编码蛋白在Notch依赖性过程中发生泛素化并加速降解。E2A编码蛋白表达的失调可能导致小鼠衰老过程中早期B淋巴细胞生成减少。
