Mitogen-activated protein kinase is involved in the progesterone-mediated induction of baboon glycodelin.
In the human and non-human primate the major secretory product of the uterine glandular epithelial cells is glycodelin. The expression of glycodelin is associated with elevated progesterone levels as its production peaks during the late luteal phase of the menstrual cycle and in early pregnancy. Consistent with our previous studies, we found that the majority of the progestin responsiveness of the baboon glycodelin promoter was retained in the -20+48 region, a region devoid of progestin- and Sp1-response elements. Using serial 5' and 3' deletions of 10 basepairs of the promoter within the pGL3Basic vector, we identified the 5' and 3' limits required for progestin responsiveness as -22 and +18, respectively. When the same regions were cloned into the pGL3Promoter vector, a construct that contains the heterologous SV40 promoter, progestin did not enhance expression. Mutation of the DNA binding domain of the progesterone receptor, which disrupts its ability to activate the progesterone response element, does not obliterate its ability to induce expression via the baboon glycodelin promoter. Inhibitors of protein tyrosine kinases, genistein and AG18, blocked the progestin-mediated induction as did an inhibitor of MEK, PD98059, but not an inhibitor of p38 MAP kinase, SB202190. These findings imply that glycodelin induction in response to progestins involves a nongenomic mechanism through the ERK1/2 branch of the MAP kinase pathway. The ultimate target may be a factor involved in the initiation of glycodelin gene transcription.
Jaffe
Randal C
RC
Department of Physiology, University of Illinois at Chicago, Illinois 60612, USA. rcjaffe@uic.edu
Ferguson-Gottschall
Susan D
SD
Fazleabas
Asgerally T
AT
D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D004247:DNA / Q000032:analysis / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D019833:Genistein / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D008969:Molecular Sequence Data; D010215:Papio / Q000235:genetics* / Q000502:physiology; D011257:Pregnancy Proteins / Q000235:genetics*; D011374:Progesterone / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D020218:Response Elements / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection; D020032:Tyrphostins / Q000494:pharmacology
D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D011257:Pregnancy Proteins; D011725:Pyridines; D020032:Tyrphostins; D011374:Progesterone; D004247:DNA; D019833:Genistein; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; C060641:tyrphostin A23; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one