The role of CBP/p300 interactions and Pit-1 dimerization in the pathophysiological mechanism of combined pituitary hormone deficiency

J Clin Endocrinol Metab. 2006 Jan;91(1):239-47. doi: 10.1210/jc.2005-1211. Epub 2005 Nov 1.


Context: Combined pituitary hormone deficiency (CPHD) in humans is caused by mutations of pituitary-specific transcription factors such as Pit-1. Although many patients with CPHD have an autosomal recessive disorder caused by a Pit-1 DNA-binding mutation, there are a number of reports of mutant Pit-1 molecules that either by prediction or through experimentation bind normally to DNA.

Objective: The objective of this study was to understand the pathophysiological mechanisms of mutant Pit-1 molecules with intact DNA binding.

Design: DNA-binding and functional studies were used to assess five Pit-1 mutations: F135C, R143Q, A158P, K216E, and R271W.

Results: In gel-shift studies using well-characterized DNA-binding elements from the GH and prolactin genes, the K126E mutant displayed markedly enhanced Pit-1 dimer binding to either element, whereas the R271W mutant bound with high avidity, but only as a monomer. In contrast, the R143Q mutant was unable to bind these elements, and the F135C and A158P mutants displayed near-normal DNA-binding characteristics. We observed that CBP/p300 bound poorly to the A158P and K216E mutant Pit-1 molecules, but bound normally to the F135C, R143Q, and R271W mutants. In functional assays, CBP/p300 cotransfection with mutant Pit-1 expression vectors resulted in less transactivation of either the GH or prolactin reporter genes.

Conclusions: From these studies, we suggest that CBP/p300 recruitment and Pit-1 dimerization are necessary for Pit-1 target gene activation and are important in the pathogenesis of CPHD.

MeSH terms

  • Base Sequence
  • Cells, Cultured
  • Electrophoretic Mobility Shift Assay
  • Genes, Reporter / genetics
  • Humans
  • Hypopituitarism / genetics*
  • Luciferases / genetics
  • Models, Molecular
  • Pituitary Hormones / deficiency*
  • Protein Binding
  • Transcription Factor Pit-1 / genetics*
  • Transcriptional Activation / genetics
  • Transfection
  • p300-CBP Transcription Factors / physiology*


  • Pituitary Hormones
  • Transcription Factor Pit-1
  • Luciferases
  • p300-CBP Transcription Factors