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Pulsatile Gonadotropin-Releasing Hormone Stimulation of Gonadotropin Subunit Transcription in Rat Pituitaries: Evidence for the Involvement of Jun N-Terminal Kinase But Not p38

Division of Endocrinology and Metabolism, Department of Medicine, and the Center for Research in Reproduction, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908

Address all correspondence and requests for reprints to: Daniel J. Haisenleder, Aurbach Medical Research Building, P.O. Box 801412, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908. E-mail: djh2q{at}virginia.edu.

We investigated whether Jun N-terminal kinase (JNK) and p38 mediate gonadotropin subunit transcriptional responses to pulsatile GnRH in normal rat pituitaries. A single pulse of GnRH or vehicle was given to female rats in vivo, pituitaries collected, and phosphorylated JNK and p38 measured. GnRH stimulated an increase in JNK phosphorylation within 5 min, which peaked 15 min after GnRH (3-fold). GnRH also increased p38 phosphorylation 2.3-fold 15 min after stimulus. Rat pituitary cells were given 60-min pulses of GnRH or media plus the JNK inhibitor SP600125 (SP, 20 µM), p38 inhibitor SB203580 (20 µM), or vehicle. In vehicle-treated groups, GnRH pulses increased LHβ and FSHβ primary transcript (PT) levels 3-fold. SP suppressed both basal and GnRH-induced increases in FSHβ PT by half, but the magnitude of responses to GnRH was unchanged. In contrast, SP had no effect on basal LHβ PT but suppressed the stimulatory response to GnRH. SB203580 had no effect on the actions of GnRH on either LH or FSHβ PTs. Lβ-T2 cells were transfected with dominant/negative expression vectors for MAPK kinase (MKK)-4 and/or MKK-7 plus a rat LHβ promoter-luciferase construct. GnRH stimulated a 50-fold increase in LHβ promoter activity, and the combination of MKK-4 and -7 dominant/negatives suppressed the response by 80%. Thus, JNK (but not p38) regulates both LHβ and FSHβ transcription in a differential manner. For LHβ, JNK is essential in mediating responses to pulsatile GnRH. JNK also regulates FSHβ transcription (i.e. maintaining basal expression) but does not play a role in responses to GnRH.

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