HOMEOPROTEINS AND PITUITARY-ADENOMAS

Several transactivating factors specifically involved in the different iation and proliferation of anterior pituitary cell types have been re cently identified. Among them Pit-1 a member of the POU-domain transcr iption 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 somat otrophs, lactotrophs and thyreotrophs. The importance of Pit-1 as a re gulator in the anterior pituitary development has been further demonst rated by naturally occurring mutations or delections in dwarf mouse st rains. In the Snell and Jackson dwarf mice, the levels of Pit-1 gene e xpression are low or indetectable, GH, PRL and TSH beta gene expressio n are absent and lactotrophs, somatotrophs, and threotrophs fail to pr oliferate. 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 a nalogous to the phenotype of the Snell and Jackson dwarf mice. In chil dren who were born to healthly 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 seque nce to those observed in normal pituitary were described in human GH, PRL and TSH secreting pituitary adenomas. The Pit-1 beta isoform, rais ed 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 isofo rms was observed between tumors identified as pure GH or PRL producing tumors. The results support the existence of other transcription fact ors interacting with Pit-1 to coordinately regulate the activity of th e GH and PRL promotors in a cell specific manner. In contrast, variabl e Pit-1 expression was observed in prolactinomas, according to their s ensitivity to bromocriptine treatment. A highly significant correlatio n was indeed evidenced between the D2 receptors mRNA and the Pit-1 mRN A levels. These results raise the possibility that Pit-1 may either di rectly or indirectly affect the transcription of the D2 dopaminergic r eceptor gene. ln fact, receptors for other hypothalamic neurohormones such a GHRH and somatostatin are known to be potential Pit-1 target ge nes. Such mechanisms could be implicated in the differentiation and pr oliferation of lactotrophs and somatotrophs.