Role of Pit-1 in the gene expression of growth hormone, prolactin, and thyrotropin

Endocrinol Metab Clin North Am. 1996 Sep;25(3):523-40. doi: 10.1016/s0889-8529(05)70339-x.

Abstract

To date, nine different mutations in the Pit-1 gene resulting in CPHD have been described in mammals. Four of these mutations alter residues important for DNA binding or alter the predicted alpha helical nature of the Pit-1 protein (A158P, R172X, E250X, and W261C). The A158P mutation, however, has minimal effects on DNA binding. Four mutations lie outside alpha helical regions (P24L, R143Q, K216E, and R271W) and do not significantly alter DNA binding either experimentally or by prediction. One mutation is a large deletion of the Pit-1 gene locus in the Jackson dwarf mouse. Mutant Pit-1 proteins that do not interfere with binding cause CPHD through interference with target gene activation and regulation. The R271W mutant acts as a dominant inhibitor of transcription of the GH and Prl genes. The A158P mutant is incapable of activating transcription from the GH-I site and has low activation of transcription of the distal enhancer and proximal promoter sites of Prl and of 320 bp of the 5' GH promoter sequence. Some mutant proteins interfere with nuclear receptors. For example, the K216E mutant has defective retinoic acid signaling on the Pit-1 gene enhancer. There is phenotypic variability in the degree of CPHD and in pituitary size in patients with Pit-1 gene mutations. Since Pit-1 has different functions in the somatotroph, lactotroph, and thyrotroph, it is not surprising that point mutations in different regions of the gene interfere in different ways with Pit-1 function. A mutant Pit-1 may be able to carry out its developmental role, but may be aberrant in GH and Prl gene activation or Pit-1 autoregulation. Study of Pit-1 mutations and their diverse pathophysiologic mechanisms should increase the understanding of anterior pituitary gland development and gene regulation in normal and disease states.

Publication types

  • Review

MeSH terms

  • Alternative Splicing
  • Animals
  • DNA
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Gene Expression Regulation, Developmental / genetics*
  • Genes, Regulator / genetics
  • Growth Hormone / biosynthesis*
  • Growth Hormone / genetics
  • Human Growth Hormone / biosynthesis
  • Human Growth Hormone / genetics
  • Mice
  • Mutation
  • Prolactin / biosynthesis*
  • Prolactin / genetics
  • Thyrotropin / biosynthesis*
  • Thyrotropin / genetics
  • Transcription Factor Pit-1
  • Transcription Factors / genetics
  • Transcription Factors / physiology*
  • Transcriptional Activation

Substances

  • DNA-Binding Proteins
  • Pit1 protein, mouse
  • Transcription Factor Pit-1
  • Transcription Factors
  • Human Growth Hormone
  • Prolactin
  • Thyrotropin
  • Growth Hormone
  • DNA