The epidermal growth factor-like growth factor amphiregulin is strongly induced by the adenosine 3',5'-monophosphate pathway in various cell types.
We examined the cAMP-mediated regulation of the epidermal growth factor-like growth factor amphiregulin (AR) in T cells and observed a strong cAMP-induced up-regulation of AR mRNA in a time- and concentration-dependent manner independent of T cell activation. This regulation may be mediated in part through activation of a cAMP-responsive element in the AR promoter, because the cAMP-responsive element conferred cAMP responsiveness to a luciferase reporter in Jurkat TAg cells. Similar effects of AR mRNA induction were seen in T cells treated with cAMP-elevating agents such as prostaglandin E(2) and forskolin as well as with the phosphodiesterase inhibitors rolipram and isobutylmethylxanthine. Furthermore, the induction of AR mRNA by cAMP was strongly suppressed by a protein kinase A type I-selective inhibitor, whereas treatment with an exchange protein directly activated by cAMP-specific agonist did not increase AR levels. In addition, an increase in AR gene transcripts by cAMP was seen in MCF-7 mammary carcinoma cells and H295R adrenal cells. Moreover, the potent cAMP-mediated induction of AR mRNA resulted in increased secretion (5-fold) of AR from T cells. Furthermore, supernatants from cAMP-stimulated T cells containing secreted AR induced phosphorylated MAPK in OVCAR-3 carcinoma cells. In conclusion, our data suggest that AR is under strong regulation by the cAMP pathway in various cell types, and that prostaglandin E(2)- and cAMP-induced AR secretion from T cells may be highly relevant in a microenvironment consisting of tumor cells and infiltrated immune cells, because AR by activating the MAPK pathway through a paracrine route may contribute to proliferation of tumor cells and thus add to neoplastic processes.
Johansson
C Christian
CC
Biotechnology Center of Oslo, University of Oslo, P.O. Box 1125, Blindern, N-0317 Oslo, Norway. kjetil.tasken@biotek.uio.no
Yndestad
Arne
A
Enserink
Jorrit M
JM
Ree
Anne H
AH
Aukrust
Pål
P
Taskén
Kjetil
K
D000262:Adenylyl Cyclases / Q000378:metabolism; D000311:Adrenal Glands / Q000166:cytology; D066258:Amphiregulin; D001943:Breast Neoplasms; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D010051:Ovarian Neoplasms; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000502:physiology; D011471:Prostatic Neoplasms; D012333:RNA, Messenger / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D014407:Tumor Cells, Cultured
C587848:AREG protein, human; D066258:Amphiregulin; D017362:Cyclic AMP Response Element-Binding Protein; D066255:EGF Family of Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D004815:Epidermal Growth Factor; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D015232:Dinoprostone