Requirement for geranylgeranyl transferase I and acyl transferase in the TGF-beta-stimulated pathway leading to elastin mRNA stabilization.
The TGF-betas are multipotent in their biological activity, modulating cell growth and differentiation as well as extracellular matrix deposition and degradation. Most of these activities involve modulation of gene transcription. However, TGF-beta1 has been shown previously to substantially increase the expression of elastin by stabilization of tropoelastin mRNA through a signaling pathway which involves a phosphatidylcholine-specific phospholipase and a protein kinase C. The present results, through the use of specific inhibitors of geranylgeranyl transferase I, farnesyl transferase, and acyl transferase, demonstrate that geranylgeranylated and acylated, but not farnesyslated protein(s) is required for this TGF-beta1 effect. In addition, the general tyrosine kinase inhibitor genistein completely blocked this TGF-beta1 effect. The results suggest that the TGF-beta1 signaling pathway requires not only receptor ser/thr kinase activity, but also tyrosine kinase and small GTPase activities.
Kucich
U
U
Department of Anatomy and Histology, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania, 19104, USA.
Rosenbloom
J C
JC
Shen
G
G
Abrams
W R
WR
Blaskovich
M A
MA
Hamilton
A D
AD
Ohkanda
J
J
Sebti
S M
SM
Rosenbloom
J
J
D000217:Acyltransferases / Q000378:metabolism*; D019883:Alkyl and Aryl Transferases / Q000378:metabolism*; D001549:Benzamides / Q000494:pharmacology; D002460:Cell Line; D002772:Cholera Toxin / Q000494:pharmacology; D004549:Elastin / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006801:Humans; D008168:Lung; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D017368:Protein Prenylation / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014333:Tropoelastin / Q000235:genetics*; D010738:Type C Phospholipases / Q000378:metabolism; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D001549:Benzamides; D004791:Enzyme Inhibitors; C096856:FTI 277; C102521:GGTI 298; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014333:Tropoelastin; D010566:Virulence Factors, Bordetella; D004549:Elastin; D002772:Cholera Toxin; D008715:Methionine; D000217:Acyltransferases; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D011493:Protein Kinase C; D010738:Type C Phospholipases; C105598:phosphatidylcholine-specific phospholipase C; D020558:GTP Phosphohydrolases