Involvement of the pituitary-specific transcription factor pit-1 in somatolactotrope cell growth and death: an approach using dominant-negative pit-1 mutants.

Abstract

The anterior pituitary-specific transcription factor Pit-1 was initially identified and cloned as a transactivator of the prolactin (PRL) and GH genes and later as a regulator of the TSHb gene. It was found to be a major developmental regulator, because natural Pit-1 gene mutations cause a dwarf phenotype in mice and cause combined pituitary hormone deficiency associated with pituitary hypoplasia in humans. To further investigate the growth-promoting effects of Pit-1, we used a strategy based on the use of dominant-negative Pit-1 mutants as an alternative means of inactivating endogenous Pit-1 functions. R271W, a Pit-1 mutant identified in one allele in patients with severe combined pituitary hormone deficiency, and Pit-1Delta1-123, a deletion mutant in which only the DNA binding domain of Pit-1 is conserved, were generated, and their ability to abolish the effects of the endogenous native Pit-1 in the differentiated proliferating somatolactotrope GH4C1 cell line was investigated. Enforced expression of the dominant-negative mutants in GH4C1 cells using recombinant lentiviral vectors decreased the levels of expression of known Pit-1 target genes such as PRL and GH, abolished the hormone release, and reduced cell viability by decreasing the growth rate and inducing apoptosis via a caspase-independent pathway. These results show for the first time that the growth-promoting effects of Pit-1 are at least partly due to the fact that this transcription factor prevents apoptotic cell death.

• Authors: Isabelle Pellegrini, Cathy Roche, Marie-Helene Quentien, Mireille Ferrand, Ginette Gunz, Sylvie Thirion, Claude Bagnis, Alain Enjalbert, Jean-Louis Franc
• Journal: Molecular endocrinology (Baltimore, Md.) (Mol Endocrinol) Vol. 20 Issue 12 Pg. 3212-27 (Dec 2006) ISSN: 0888-8809 [Print] United States
• PMID: 16901973 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Pituitary Hormones
• Transcription Factor Pit-1

Topics

• Apoptosis (genetics)
• Cell Death (genetics)
• Cell Proliferation
• Cells, Cultured
• Dwarfism, Pituitary (genetics)
• Gene Expression Regulation
• Gene Transfer Techniques
• Humans
• Lentivirus (genetics)
• Mutation
• Pituitary Hormones (deficiency, metabolism)
• Transcription Factor Pit-1 (genetics, physiology)
• Transfection