Pit-1 Gene Expression in Human Pituitary Adenomas

Abstract

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 TSHβ gene. Analysis of Pit-1 expression during mouse embryogenesis revealed that initiation of its expression correlates both temporally and spatially with activation of its target genes. Immunocytochemical studies revealed a high expression of Pit-1 protein in the nuclei of only three cell types: somatotropes, lactotropes and thyrotropes. The importance of Pit-1 as a regulator of the anterior pituitary development has been further demonstrated by the absence of somatotropes, lactotropes and thyrotropes in the pituitary glands of Pit-1-defective mice and humans. Since Pit-1 is required for both cell phenotype and proliferation, one may ask if this transcription factor might be associated with development of pituitary tumors. Several investigators have reported Pit-1 gene expression in human pituitary adenomas. These studies, while not in total agreement, show that pituitary tumorigenesis does not seem to be associated 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 transcripts correlated with the localization of Pit-1 protein. The biological relevance of Pit-1 expression reported in some nonfunctioning adenomas remains to be clarified. As expression of the PRL and GH genes is ultimately confined to distinct lactotropic and somatotropic populations despite 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-1β 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. This form could, at least in part, account for the cell-specific activation of the PRL and GH genes. Pit-1β was invariably found present in all the tumors expressing the Pit-1 major form, no significant difference in the Pit-1 β/Pit-1 expression ratio being observed between tumors identified as pure 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 for the β-isoform in the cell type-specific expression of the GH and PRL genes in humans. The failure of somatotropes, lactotropes and thyrotropes to proliferate in Pit-1-defective mice and humans indicates that Pit-1 might be competent to activate genes required for cell proliferation or survival of the three cell types. Recent data indeed suggest that Pit-1 may directly or indirectly regulate somatotropes and lactotropes through activation of the receptors for GRF and SRIF on the one hand, and dopamine on the other hand. Such regulatory mechanisms could contribute to the differentiation of the somatomammotropic lineage in ful...

Abnormal Transduction Mechanisms in Pituitary Adenomas

“…They are identical in size and sequence in adenomas and in normal pituitary [54], No mutations of Pit-1 gene have been detected in the pitu itary adenomas. Furthermore, the Pit-1 mRNA levels are not quantitatively different in somatotroph and lactotroph adenomas [54][55][56], Pit-1 gene expression was also analyzed in a series of PRL-sccrcting tumors presenting with a variable response to bromocriptine treatment. Quantitative analysis by Northern blot showed that Pit-1 mRNA levels were lower in the tumor presenting with a decreased response to the dopaminergic agonist.…”

POU Domain Factors in the Neuroendocrine System: Lessons from Developmental Biology Provide Insights into Human Disease*

“…As in the Brn-4 (Ϫ/Ϫ) mouse, no metabolic changes have been reported in these individuals, but specific metabolic tests might be needed to detect subtle differences. No major abnormalities in the amount or form of Pit-1 transcripts have been observed in these tumors, and Pit-1 mRNA levels seem to be similar in somatotrope and lactotrope adenomas (382,385). No major abnormalities in the amount or form of Pit-1 transcripts have been observed in these tumors, and Pit-1 mRNA levels seem to be similar in somatotrope and lactotrope adenomas (382,385).…”

PIT1 upregulation by HMGA proteins has a role in pituitary tumorigenesis

“…Interestingly, high expression levels of PIT1 represent a constant feature of human pituitary GH, PRL and TSH adenomas (Asa et al 1993, Delhase et al 1993, Friend et al 1993, Pellegrini et al 1994, Pellegrini-Bouiller et al 1997, and several previous studies suggested a potential role for PIT1 in cell proliferation, the prevention of apoptotic death and the pathogenesis of pituitary tumours (Castrillo et al 1991, Gaiddon et al 1999, Salvatori et al 2002, Pellegrini et al 2006. In fact, microinjection of Pit1 antisense sequences blocks cell growth in the GC somatotroph cell line (Castrillo et al 1991) and dominant-negative mutants of Pit1 reduce cell viability by decreasing the growth rate and inducing apoptosis via a caspaseindependent pathway (Pellegrini et al 2006).…”

“…PIT1, also named GHF1, is a member of the POU transcription factor family (Delhase et al 1996), and plays a key role in the specification, expansion and survival of three specific pituitary cell types (somatotropes, lactotropes and a subset of thyrotropes) during the development of the anterior pituitary (Lefevre et al 1987, Nelson et al 1988, Li et al 1990, and its transcriptional activity on many genes, such as GH, PRL, TSHB, GHRHR and PIT1 itself, is crucial for pituitary gland physiology (Lefevre et al 1987, Nelson et al 1988, Chen et al 1990, Li et al 1990, McCormick et al 1990. Moreover, PIT1 is overexpressed in GH, PRL and TSH pituitary adenomas (Asa et al 1993, Delhase et al 1993, Friend et al 1993, Pellegrini et al 1994, Pellegrini-Bouiller et al 1997.…”