Transforming growth factor-beta induces the expression of ANF and hypertrophic growth in cultured cardiomyoblast cells through ZAK.
Transforming growth factor-beta (TGF-beta) has been associated with the onset of cardiac cell hypertrophy, but the mechanisms underlying this dissociation are not completely understood. By a previous study, we investigated the involvement of a MAP3K, ZAK, which in cultured H9c2 cardiac cells is a positive mediator of cell hypertrophy. Our results showed that expression of a dominant-negative form of ZAK inhibited the characteristic TGF-beta-induced features of cardiac hypertrophy, including increased cell size, elevated expression of atrial natriuretic factor (ANF), and increased organization of actin fibers. Furthermore, dominant-negative MKK7 effectively blocked both TGF-beta-and ZAK-induced ANF expression. In contrast, a JNK/SAPK specific inhibitor, sp600125, had little effect on TGF-beta- or ZAK-induced ANF expression. Our findings suggest that a ZAK mediates TGF-beta-induced cardiac hypertrophic growth via a novel TGF-beta signaling pathway that can be summarized as TGF-beta>ZAK>MKK7>ANF.
Huang
Chih-Yang
CY
Institute of Biochemistry, Chung-Shan Medical University, Taichung 402, Taiwan.
Kuo
Wei-Wen
WW
Chueh
Pin Ju
PJ
Tseng
Chien-Tang
CT
Chou
Ming-Yung
MY
Yang
Jaw-Ji
JJ
D000199:Actins / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism*; D048429:Cell Size; D002478:Cells, Cultured; D006801:Humans; D006984:Hypertrophy; D007378:Interleukins / Q000494:pharmacology; D048688:MAP Kinase Kinase 7 / Q000235:genetics / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000473:pathology* / Q000502:physiology*; D010656:Phenylephrine / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D000199:Actins; D000873:Anthracenes; D007378:Interleukins; D047428:Protein Kinase Inhibitors; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; C432165:pyrazolanthrone; D010656:Phenylephrine; D009320:Atrial Natriuretic Factor; D011494:Protein Kinases; D020930:MAP Kinase Kinase Kinases; C413047:MAP3K20 protein, human; D048688:MAP Kinase Kinase 7; C482569:MAP2K7 protein, human