Monoclonal Antibodies Specific for STAT3β Reveal Its Contribution to Constitutive STAT3 Phosphorylation in Breast Cancer.
Monoclonal Antibodies Specific for STAT3β Reveal Its Contribution to Constitutive STAT3 Phosphorylation in Breast Cancer.
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DOI：
10.3390/cancers6042012
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发表时间：
2014-09-29
期刊：
影响因子：
5.2
通讯作者：
Tweardy DJ
中科院分区：
文献类型：
--
作者：
Bharadwaj U;Kasembeli MM;Eckols TK;Kolosov M;Lang P;Christensen K;Edwards DP;Tweardy DJ
自从19年前在小鼠和人类身上发现STAT3以来，选择性剪接的STAT3，STAT3β对STAT3整体功能的贡献一直存在争议。与pSTAT3β同源二聚体相比，酪氨酸磷酸化的(P)STAT3DNA同源二聚体更稳定，结合α更强烈，对去磷酸化更不敏感，并表现出明显的细胞内动力学，最显著的是延长了核保留。在细胞系中过表达一种或另一种亚型表明，STAT3β在转化试验中起着STAT3α显性阴性的作用；然而，对缺乏一种或另一种亚型的小鼠品系的研究表明，STAT3亚型对炎症有明显的贡献。目前的免疫学试剂不能区分STAT3β的选择性剪接和蛋白水解性切割所产生的α蛋白。我们研制的单抗能够识别信号转导蛋白3β(CT7)特有的7个C末端氨基酸，并且不与信号转导信号转导蛋白3α发生交叉反应。免疫印迹研究表明，乳腺癌细胞系中STAT3β蛋白的表达水平与pSTAT3的总体水平呈正相关，提示STAT3α可能参与了该肿瘤系统中STAT3的结构性激活。明确区分剪接替代STAT3β和蛋白水解性STAT3β和STAT3α的能力将为研究STAT3β和STAT3α在肿瘤发生以及其他生物和病理过程中的作用提供新的见解。
Since its discovery in mice and humans 19 years ago, the contribution of alternatively spliced Stat3, Stat3β, to the overall functions of Stat3 has been controversial. Tyrosine-phosphorylated (p) Stat3β homodimers are more stable, bind DNA more avidly, are less susceptible to dephosphorylation, and exhibit distinct intracellular dynamics, most notably markedly prolonged nuclear retention, compared to pStat3α homodimers. Overexpression of one or the other isoform in cell lines demonstrated that Stat3β acted as a dominant-negative of Stat3α in transformation assays; however, studies with mouse strains deficient in one or the other isoform indicated distinct contributions of Stat3 isoforms to inflammation. Current immunological reagents cannot differentiate Stat3β proteins derived from alternative splicing vs. proteolytic cleavage of Stat3α. We developed monoclonal antibodies that recognize the 7 C-terminal amino acids unique to Stat3β (CT7) and do not cross-react with Stat3α. Immunoblotting studies revealed that levels of Stat3β protein, but not Stat3α, in breast cancer cell lines positively correlated with overall pStat3 levels, suggesting that Stat3β may contribute to constitutive Stat3 activation in this tumor system. The ability to unambiguously discriminate splice alternative Stat3β from proteolytic Stat3β and Stat3α will provide new insights into the contribution of Stat3β vs. Stat3α to oncogenesis, as well as other biological and pathological processes.
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影响因子：
3.7
作者：
Alten, Jeffrey A.;Moran, Ana;Tweardy, David J.
通讯作者：
Tweardy, David J.
DOI：
10.1111/j.1749-6632.1982.tb22124.x
发表时间：
1982-01-01
影响因子：
5.2
作者：
KUSHNER, I
通讯作者：
KUSHNER, I
DOI：
10.1073/pnas.122236099
发表时间：
2002-06-11
影响因子：
11.1
作者：
Costa-Pereira, AP;Tininini, S;Poli, V
通讯作者：
Poli, V
影响因子：
5.2
作者：
Bharadwaj, Uddalak;Li, Min;Yao, Qizhi
通讯作者：
Yao, Qizhi
影响因子：
4.8
作者：
Caldenhoven, E;vanDijk, TB;deGroot, RP
通讯作者：
deGroot, RP