Constitutive activation of JAK-STAT3 signaling by BRCA1 in human prostate cancer cells.
Germ-line mutations of the breast cancer susceptibility gene 1 (BRCA1) confer a high risk for breast and ovarian cancer in women and prostate cancer in men. The BRCA1 protein contributes to cell proliferation, cell cycle regulation, DNA repair and apoptosis; however, the mechanisms underlying these functions of BRCA1 remain largely unknown. Here, we showed that, in Du-145 human prostate cancer cells, enhanced expression of BRCA1 resulted in constitutive activation of signal transducer and activator transcription factor 3 (STAT3) tyrosine and serine phosphorylation. Moreover, Janus kinase 1 (JAK1) and JAK2, the upstream activators of STAT3, were also activated by BRCA1. Immunoprecipitation assay showed that BRCA1 interacted with JAK1 and JAK2. Blocking STAT3 activation using antisense oligonucleotides significantly inhibited cell proliferation and triggered apoptosis in Du-145 cells with enhanced expression of BRCA1. These findings indicate that BRCA1 interacts with the components of the JAK-STAT signaling cascade and modulates its activation, which may provide a new critical survival signal for the growth of breast, ovarian and prostate cancers in the presence of normal BRCA1.
Gao
B
B
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298, USA. bgao@mail.nih.gov
Shen
X
X
Kunos
G
G
Meng
Q
Q
Goldberg
I D
ID
Rosen
E M
EM
Fan
S
S
D017209:Apoptosis; D019313:BRCA1 Protein / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002455:Cell Division; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D019398:Genes, BRCA1 / Q000235:genetics; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D008297:Male; D016376:Oligonucleotides, Antisense / Q000235:genetics; D010766:Phosphorylation; D011233:Precipitin Tests; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured
D019313:BRCA1 Protein; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D015534:Trans-Activators; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2