Testicular leukemia inhibitory factor (LIF) and LIF receptor (LIFR) mediate phosphorylation of STAT-3 and STAT-1 proteins and induce c-fos transcription and AP-1 activation in rat Sertoli but not germ cells
Jenab,Shirzad; Morris,Patricia L.
Endocrinology 139(4): 1883-1890
Publication date: 1998
Increasing amounts of evidence suggest noninflammatory rolesfor growth factor and cytokines in development and differentiation.Leukemia inhibitory factor (LIF) belongs to a gp130 pleiotropicfamily of growth factors that has recently been shown to enhancethe survival of rat testicular gonocytes and Sertoli cells.In this study, we show the expression of gp130 and LIF messengerRNAs (mRNAs) in the somatic (the Sertoli and Leydig cells) andspecific germ cells (spermatogonia, pachytene, round, and elongatedspermatids) of rodent testis, suggestive of cell-specific LIF-mediatedfunctions. LIF receptor mRNA was demonstrated in rat somaticcells, rat elongating spermatids, and all of the mouse germcells. In addition, we characterized the effects of LIF on thesignal transducers and activators of transcription (STAT)-3and STAT-1, c-fos gene expression, and activator protein-1 regulationin primary rat Sertoli cells. Electrophoretic mobility shiftassay and Western blot analysis demonstrated that LIF translocatesSTAT-3 (and to a lesser extent STAT-1) transcription factor(s)to the nucleus within 2 min of exposure in a tyrosine but notserine/threonine phosphorylation-dependent pathway. Quantitativesolution hybridization analysis revealed a transient increasein c-fos mRNA levels by 20-fold following 30-45 min ofLIF treatment, an effect that was inhibited by the tyrosine,as well as serine/threonine kinase inhibitors, genistein, andH7. Subsequently, LIF treatment of the Sertoli cells increased nuclearactivator protein-1 binding proteins at 2 h after its addition,an effect that was also sensitive to genistein and H7 pretreatments.In contrast, LIF treatment of primary rat germ cells did notalter c-fos mRNA levels. Species specificity in the expressionof LIF receptor as well as ligand binding may play a role in LIFsignaling in these germ cells. Thus, using a primary Sertolicell model, we demonstrated that the testicular LIF signalingpathway is contingent on the phosphorylation of latent transcriptionfactors. Our data are consistent with LIF-mediated signalingevents involving both somatic and germ cells during spermatogenesis.