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The Role of CBP/p300 Interactions and Pit-1 Dimerization in the Pathophysiological Mechanism of Combined Pituitary Hormone Deficiency

Sections of Pediatric and Adult Endocrinology, Department of Pediatrics and Medicine, University of Chicago, Pritzker School of Medicine, Chicago, Illinois 60637

Address all correspondence and requests for reprints to: Dr. Ronald Cohen, Section of Endocrinology, Department of Medicine, University of Chicago, 5841 South Maryland Avenue, MC 1027, Chicago, Illinois 60637. E-mail: roncohen{at}medicine.bsd.uchicago.edu.

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.

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