[Homeoproteins and pituitary adenoma]

Several transactivating factors specifically involved in the differentiation and proliferation of anterior pituitary cell types have been recently identified. Among them Pit-1 a member of the POU-domain transcription factors family is specific of anterior pituitary cells, and was initially identified and cloned as a transactivator of the GH and PRL genes and as a regulator of the TSH beta gene. Pit-1 play a key role during embryogenesis in the differentiation and proliferation of somatotrophs, lactotrophs and thyreotrophs. The importance of Pit-1 as a regulator in the anterior pituitary development has been further demonstrated by naturally occurring mutations or delections in dwarf mouse strains. In the Snell and Jackson dwarf mice, the levels of Pit-1 gene expression are low or undetectable, GH, PRL and TSH beta gene expression are absent and lactotrophs, somatotrophs, and threotrophs fail to proliferate. Furthermore Pit-1 carries out similar functions in humans. This is supported by the fact that children with mutations of the Pit-1 gene present with a congenital combined GH, PRL and TSH deficiency analogous to the phenotype of the Snell and Jackson dwarf mice. In children who were born to healthy consanguinous parents and present such combined deficiencies we recently reported a Pit-1 mutation causing a transition from a Phe to a Cys in a region of the protein known to be involved in DNA binding. 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. The Pit-1 beta isoform, raised through alternative splicing of exon 2 of the Pit-1 gene, is a more potent inducer of GH transcription than the major Pit-1 form. However no difference in the level of expression of the different Pit-1 isoforms was observed between tumors identified as pure GH or PRL producing tumors. The results support the existence of other transcription factors interacting with Pit-1 to coordinately regulate the activity of the GH and PRL promotors in a cell specific manner. In contrast, variable Pit-1 expression was observed in prolactinomas, according to their sensitivity to bromocriptine treatment. A highly significant correlation was indeed evidenced between the D2 receptors mRNA and the Pit-1 mRNA levels. These results raise the possibility that Pit-1 may either directly or indirectly affect the transcription of the D2 dopaminergic receptor gene. In fact, receptors for other hypothalamic neurohormones such a GHRH and somatostatin are known to be potential Pit-1 target genes. Such mechanisms could be implicated in the differentiation and proliferation of lactotrophs and somatotrophs.