Monoclonal Antibodies Specific for STAT3β Reveal Its Contribution to Constitutive STAT3 Phosphorylation in Breast Cancer

被引:16
作者
Bharadwaj, Uddalak [1 ]
Kasembeli, Moses M. [1 ]
Eckols, T. Kris [1 ]
Kolosov, Mikhail [1 ]
Lang, Paul [1 ]
Christensen, Kurt [2 ]
Edwards, Dean P. [2 ,3 ]
Tweardy, David J. [1 ,2 ,4 ]
机构
[1] Baylor Coll Med, Dept Med, Infect Dis Sect, Houston, TX 77030 USA
[2] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA
[3] Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA
[4] Baylor Coll Med, Dept Biochem & Mol Biol, Houston, TX 77030 USA
来源
CANCERS | 2014年 / 6卷 / 04期
基金
美国国家卫生研究院;
关键词
Stat3; beta; isoform; alternative RNA splicing; CT7; phosphorylation; monoclonal; oncogenesis; breast cancer; regulation; COLONY-STIMULATING FACTOR; HUMAN PANCREATIC-CANCER; ACUTE MYELOID-LEUKEMIA; NF-KAPPA-B; SIGNAL TRANSDUCER; SUPPRESSES GROWTH; GENE-EXPRESSION; CELL-PROLIFERATION; NUCLEAR RETENTION; ACTIVATED STAT3;
D O I
10.3390/cancers6042012
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Since its discovery in mice and humans 19 years ago, the contribution of alternatively spliced Stat3, Stat3 beta, to the overall functions of Stat3 has been controversial. Tyrosine-phosphorylated (p) Stat3 beta 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 pStat3 alpha homodimers. Overexpression of one or the other isoform in cell lines demonstrated that Stat3 beta acted as a dominant-negative of Stat3 alpha 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 Stat3 beta proteins derived from alternative splicing vs. proteolytic cleavage of Stat3 alpha. We developed monoclonal antibodies that recognize the 7 C-terminal amino acids unique to Stat3 beta (CT7) and do not cross-react with Stat3 alpha. Immunoblotting studies revealed that levels of Stat3 beta protein, but not Stat3 alpha, in breast cancer cell lines positively correlated with overall pStat3 levels, suggesting that Stat3 beta may contribute to constitutive Stat3 activation in this tumor system. The ability to unambiguously discriminate splice alternative Stat3 beta from proteolytic Stat3 beta and Stat3 alpha will provide new insights into the contribution of Stat3 beta vs. Stat3 alpha to oncogenesis, as well as other biological and pathological processes.
引用
收藏
页码:2012 / 2034
页数:23
相关论文
共 50 条
[31]   Roads to Stat3 Paved with Cadherins [J].
Adan, Hanad ;
Daniel, Juliet ;
Raptis, Leda .
CELLS, 2022, 11 (16)
[32]   Direct Targeting Options for STAT3 and STAT5 in Cancer [J].
Orlova, Anna ;
Wagner, Christina ;
de Araujo, Elvin D. ;
Bajusz, David ;
Neubauer, Heidi A. ;
Herling, Marco ;
Gunning, Patrick T. ;
Keseru, Gyorgy M. ;
Moriggl, Richard .
CANCERS, 2019, 11 (12)
[33]   Roles of STAT3 in leukemia [J].
Shi, Yin ;
Zhang, Zhen ;
Qu, Xintao ;
Zhu, Xiaoxiao ;
Zhao, Lin ;
Wei, Ran ;
Guo, Qiang ;
Sun, Linlin ;
Yin, Xunqiang ;
Zhang, Yunhong ;
Li, Xia .
INTERNATIONAL JOURNAL OF ONCOLOGY, 2018, 53 (01) :7-20
[34]   JAKi rips STAT3 in cancer [J].
Greten, Florian R. ;
Karin, Michael .
NATURE MEDICINE, 2010, 16 (10) :1085-1087
[35]   STAT3: a multifaceted oncoprotein [J].
Guanizo, Aleks C. ;
Fernando, Chamira Dilanka ;
Garama, Daniel J. ;
Gough, Daniel J. .
GROWTH FACTORS, 2018, 36 (1-2) :1-14
[36]   STAT3 pathway as a molecular target for resveratrol in breast cancer treatment [J].
Kohandel, Zeynab ;
Farkhondeh, Tahereh ;
Aschner, Michael ;
Pourbagher-Shahri, Ali Mohammad ;
Samarghandian, Saeed .
CANCER CELL INTERNATIONAL, 2021, 21 (01)
[37]   Targeting STAT3 in gastric cancer [J].
Giraud, Andrew S. ;
Menheniott, Trevelyan R. ;
Judd, Louise M. .
EXPERT OPINION ON THERAPEUTIC TARGETS, 2012, 16 (09) :889-901
[38]   A Fluorescent Reporter of the Phosphorylation Status of the Substrate Protein STAT3 [J].
Lacey, Vanessa K. ;
Parrish, Angela R. ;
Han, Shuliang ;
Shen, Zhouxin ;
Briggs, Steven P. ;
Ma, Yuguo ;
Wang, Lei .
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, 2011, 50 (37) :8692-8696
[39]   Overexpression of Stat3 increases circulating cfDNA in breast cancer [J].
Yi-Fei Wang ;
Xue-Jian Wang ;
Zhong Lu ;
Shu-Rong Liu ;
Yu Jiang ;
Xiao-Qing Wan ;
Cong-Cong Cheng ;
Li-Hong Shi ;
Li-Hua Wang ;
Yi Ding .
Breast Cancer Research and Treatment, 2021, 187 :69-80
[40]   DDIAS promotes STAT3 activation by preventing STAT3 recruitment to PTPRM in lung cancer cells [J].
Im, Joo-Young ;
Kim, Bo-Kyung ;
Lee, Kang-Woo ;
Chun, So-Young ;
Kang, Mi-Jung ;
Won, Misun .
ONCOGENESIS, 2020, 9 (01)