PIT-1 GENE-EXPRESSION IN HUMAN PITUITARY-ADENOMAS

The anterior pituitary-specific transcription factor Pit-1 (also known as GHF-1) was initially identified and cloned as a transactivator of the GH and PRL genes, and later as a regulator of the TSH beta gene. A nalysis of Pit-1 expression during mouse embryogenesis revealed that i nitiation of its expression correlates both temporally and spatially w ith activation of its target genes. Immunocytochemical studies reveale d a high expression of Pit-1 protein in the nuclei of only three cell types: somatotropes, lactotropes and thyrotropes. The importance of Pi t-1 as a regulator of the anterior pituitary development has been furt her demonstrated by the absence of somatotropes, lactotropes and thyro tropes in the pituitary glands of Pit-1-defective mice and humans. Sin ce Pit-1 is required for both cell phenotype and proliferation, one ma y ask if this transcription factor might be associated with developmen t of pituitary tumors. Several investigators have reported Pit-1 gene expression in human pituitary adenomas. These studies, while not in to tal agreement, show that pituitary tumorigenesis does not seem to be a ssociated with a gross alteration of Pit-1 gene expression in humans. Pit-1 transcripts, identical in size and sequence to those observed in normal pituitary, were described in human GH-, PRL- and TSH-secreting pituitary adenomas and in most cases the presence of Pit-1 transcript s correlated with the localization of Pit-1 protein. The biological re levance of Pit-1 expression reported in some nonfunctioning adenomas r emains to be clarified. As expression of the PRL and GH genes is ultim ately confined to distinct lactotropic and somatotropic populations de spite the presence of Pit-1 protein in both cell types, there must be additional mechanisms that control the cell-specific activation of the PRL and GH promoters. The Pit-1 beta isoform, raised through alternat ive splicing of exon 2 of the Pit-1 gene, is a more potent inducer of GH transcription than the major Pit-1 form. This form could, at least in part, account for the cell-specific activation of the PRL, and GH g enes. Pit-1 beta was invariably found present in all the tumors expres sing the Pit-1 major form, no significant difference in the Pit-1 beta /Pit-1 expression ratio being observed between tumors identified as pu re GH- or PRL producing tumors. This lack of selectivity together with its low level of expression is therefore not in favor of a key role f or the beta-isoform in the cell type-specific expression of the GH and PRL genes in humans. The failure of somatotropes, lactotropes and thy rotropes to proliferate in Pit-1-defective mice and humans indicates t hat Pit-1 might be competent to activate genes required for cell proli feration or survival of the three cell types. Recent data indeed sugge st that Pit-1 may directly or indirectly regulate somatotropes and lac totropes through activation of the receptors for GRF and SRIF on the o ne hand, and dopamine on the other hand. Such regulatory mechanisms co uld contribute to the differentiation of the somatomammotropic lineage in fully differentiated somatotropic and lactotropic cells.