1alpha,25(OH)(2)-Vitamin D(3) stimulates intestinal cell p38 MAPK activity and increases c-Fos expression.
In intestinal cells, as in other target cells, the steroid hormone 1alpha,25(OH)(2)-Vitamin D(3) (1alpha,25(OH)(2)D(3)) regulates gene expression via the specific intracellular Vitamin D receptor and induces fast non-transcriptional responses involving stimulation of transmembrane signal transduction pathways. We have previously shown that the hormone activates the extracellular signal-regulated mitogen-activated protein (MAP) kinase isoforms ERK1 and ERK2 in rat intestinal cells. In the present study, we have demonstrated that 1alpha,25(OH)(2)D(3) also induces the phosphorylation and activation of p38 MAPK in these cells. The hormone effects were time and dose-dependent, with maximal stimulation at 2min (+3-fold) and 1nM. 1alpha,25(OH)(2)D(3)-dependent p38 phosphorylation was suppressed by SB 203580, a selective inhibitor of p38 MAPK. Ca(2+) chelation with EGTA, inhibition of the c-Src-tyrosine kinase family with PP1 or protein kinase A (PKA) with Rp-cAMP, attenuated hormone activation of p38 MAPK. The physiological significance of 1alpha,25(OH)(2)D(3)-dependent activation of ERK1/2 and p38 MAP kinases was addressed by monitoring c-Fos expression. Incubation of intestinal cells with the hormone was followed by a rapid induction of c-Fos expression which was blocked by SB 203580 and partially suppressed by the ERK1/2 inhibitor PD 98059. Our results suggest that 1alpha,25(OH)(2)D(3) activates p38 MAPK, involving Ca(2+), c-Src and PKA as upstream regulators, and that p38 MAPK has a central role in hormone-induction of the oncoprotein c-Fos in rat intestinal cells.
Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, 8000 Bahía Blanca, Argentina.
Verónica González
VG
Pardo
Ricardo
R
Boland
Ana Russo
AR
de Boland
D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002117:Calcitriol / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects; D004386:Duodenum / Q000737:chemistry / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects; D015870:Gene Expression; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D011505:Protein-Tyrosine Kinases / Q000187:drug effects; D016760:Proto-Oncogene Proteins c-fos / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018167:Receptors, Calcitriol / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000032:analysis / Q000187:drug effects*; D019061:src-Family Kinases
D016760:Proto-Oncogene Proteins c-fos; D018167:Receptors, Calcitriol; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D002117:Calcitriol