BLIMP-1 and STAT3 Counterregulate MicroRNA-21 during Plasma Cell Differentiation
BLIMP-1 and STAT3 Counterregulate MicroRNA-21 during Plasma Cell Differentiation
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DOI：
10.4049/jimmunol.1101563
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发表时间：
2012-07-01
影响因子：
4.4
通讯作者：
Doody, Gina M.
中科院分区：
文献类型：
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作者：
Barnes, Nicholas A.;Stephenson, Sophie;Doody, Gina M.
在细胞分化过程中，mRNA的转录和翻译需要精确的协调。控制这一点的机制没有得到很好的界定。IL-21是浆细胞分化的重要调节剂，并且其通过STAT 3和IRF 4控制浆细胞分化的主调节剂B淋巴细胞诱导的成熟蛋白-1（BIMP-1）。STAT 3的其他靶点是microRNA-21（miR-21）。miR-21是恶性肿瘤（包括B细胞淋巴瘤）中最常失调的microRNA，并且其在STAT 3下游具有致癌潜力。然而，miR-21在浆细胞分化过程中的调节和功能尚未表征。与在其他系统中观察到的对STAT 3激活的响应中的miR-21的诱导相反，我们证明了miR-21在IL-21驱动的浆细胞分化期间被抑制。我们探索了这种抑制的分子基础，并将主要的miR-21转录确定为BLIMP-1依赖性抑制的直接靶点，尽管持续的STAT 3激活和磷酸化STAT 3与主要的miR-21启动子结合。因此，STAT 3和BLIMP-1在IL-21下游构成了一个不相干的前馈环，可以在浆细胞分化期间协调microRNA与mRNA表达。免疫学杂志，2012，189：253-260。
During cellular differentiation, mRNA transcription and translation require precise coordination. The mechanisms controlling this are not well defined. IL-21 is an important regulator of plasma cell differentiation, and it controls the master regulator of plasma cell differentiation, B lymphocyte-induced maturation protein-1 (BLIMP-1), via STAT3 and IRF4. Among the other targets of STAT3 is microRNA-21 (miR-21). miR-21 is the most frequently deregulated microRNA in malignancy, including B cell lymphomas, and it has oncogenic potential downstream of STAT3. However, the regulation and function of miR-21 during plasma cell differentiation are not characterized. In contrast to the induction of miR-21 observed in response to STAT3 activation in other systems, we demonstrate that miR-21 is repressed during IL-21-driven plasma cell differentiation. We explored the molecular basis for this repression and identify primary miR-21 transcription as a direct target of BLIMP-1-dependent repression, despite continued STAT3 activation and phospho-STAT3 binding to the primary miR-21 promoter. Thus, STAT3 and BLIMP-1 constitute an incoherent feed-forward loop downstream of IL-21 that can coordinate microRNA with mRNA expression during plasma cell differentiation. The Journal of Immunology, 2012, 189: 253-260.