title: Downregulation of IL-6-induced STAT3 tyrosine phosphorylation by TGF-beta1 is mediated by caspase-dependent and -independent processes.
abstract: To explore the possible cross-talk between the IL-6 and TGF-beta1 pathways in AML blast cells, the effect of TGF-beta1 pretreatment on IL-6-induced STAT3 tyrosine phosphorylation was studied. A reduction of STAT3 tyrosine phosphorylation after TGF-beta1 pretreatment was observed in four out of 40 AML cases (10%), although all of the AML cases responded to TGF-beta1 by means of SMAD3 translocation. The reduced IL-6-mediated STAT3 tyrosine phosphorylation after pre-treatment with TGF-beta1 was associated with apoptosis and coincided with the degradation of certain cellular proteins, including JAK1 and -2 and Tyk2, without affecting the ERK expression and phosphorylation. Furthermore, treatment of AML blasts with the cytostatic agent VP16, as an alternative way to induce apoptosis, resulted in a similar degree of degradation of JAK kinases and concomitant reduction of IL-6-mediated STAT3 tyrosine phosphorylation. Although degradation of JAK kinases could be rescued by incubating the cells with the pan-caspase inhibitor Z-VAD-fmk, the attenuating effect of TGF-beta1 treatment on the STAT3 tyrosine phosphorylation was still partly present. It was shown that in AML cells cultured in the presence of Z-VAD-fmk, TGF-beta1 pretreatment resulted in a reduction of JAK1 phosphorylation upon IL-6 stimulation. Expression of SOCS1 and -3 could be ruled out as a possible cause of reduced JAK1 phosphorylation levels in the investigated AML case.
authors.affiliation: University Hospital Groningen, Dept of Hematology, Groningen, The Netherlands.
authors.forename: A T J
authors.initials: AT
authors.lastname: Wierenga
authors.forename: J J
authors.initials: JJ
authors.lastname: Schuringa
authors.forename: B J L
authors.initials: BJ
authors.lastname: Eggen
authors.forename: W
authors.initials: W
authors.lastname: Kruijer
authors.forename: E
authors.initials: E
authors.lastname: Vellenga
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017304:Annexin A5 / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins / Q000378:metabolism*; D015536:Down-Regulation; D024202:Electrophoretic Mobility Shift Assay; D004847:Epithelial Cells / Q000187:drug effects; D005047:Etoposide / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins; D053613:Janus Kinase 1; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D021381:Protein Transport; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D051900:Smad3 Protein; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D017304:Annexin A5; D000972:Antineoplastic Agents, Phytogenic; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D012097:Repressor Proteins; C497790:SMAD3 protein, human; C108944:SOCS1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051900:Smad3 Protein; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C508960:TGFB1 protein, human; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D014443:Tyrosine; D005047:Etoposide; D011505:Protein-Tyrosine Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases