Comparison of leptin- and interleukin-6-regulated expression of the rPAP gene family: evidence for differential co-regulatory signals.
The pancreatitis-associated protein (PAP)/regenerating protein (REG) family represents a complex group of small secretory proteins, which can function as acute phase reactants, lectins, antiapoptotic factors or growth factors for pancreatic beta-cells and neural cells. Transcriptional induction of rPAP/Reg genes was studied here in PC12 cells made responsive to leptin. Northern-blots showed quantitative differences in induction of four major family members by leptin and IL-6. Surprisingly, induction by leptin was strongly enhanced upon forskolin co-treatment whereas induction by IL-6 was counteracted. Functional studies involving progressive rPAP I promoter deletions showed, in the case of leptin, a clear correlation with predicted cis-regulatory elements. Leptin-induced stimulation was dependent on STAT3, since over-expression of dominant-negative STAT3, but not of dominant-negative STAT1, completely blocked transcriptional activation. In case of IL-6, an enhancer element outside the cloned promoter fragment is required for full stimulation. The effects of forskolin in a leptin and IL-6 context could not be explained at the promoter level, but rather events occurring upstream in the signalling cascade must be postulated to explain the differential co-regulatory effects.
Broekaert
Daniël
D
Department VIB09, Medical Protein Research, Flanders' Interuniversity Institute for Biotechnology, Faculty of Medicine and Health Sciences, Ghent University, Albert Bartsoenkaai 3, B-9000 Ghent, Belgium.
Eyckerman
Sven
S
Lavens
Delphine
D
Verhee
Annick
A
Waelput
Wim
W
Vandekerckhove
Joël
J
Tavernier
Jan
J
D000209:Acute-Phase Proteins / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D002460:Cell Line; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D015850:Interleukin-6 / Q000494:pharmacology*; D037181:Lectins, C-Type; D020738:Leptin / Q000494:pharmacology*; D000073718:Pancreatitis-Associated Proteins; D051381:Rats; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation
D000209:Acute-Phase Proteins; D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D037181:Lectins, C-Type; D020738:Leptin; D000073718:Pancreatitis-Associated Proteins; C000612141:REG3A protein, human; C000612144:Reg3b protein, rat; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D015534:Trans-Activators; D005576:Colforsin