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Molecular and Cellular Biology, November 2006, p. 8087-8098, Vol. 26, No. 21
0270-7306/06/$08.00+0     doi:10.1128/MCB.02410-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Dynamic Interactions between Pit-1 and C/EBP{alpha} in the Pituitary Cell Nucleus{triangledown}

Ignacio A. Demarco, Ty C. Voss,{dagger} Cynthia F. Booker, and Richard N. Day*

Departments of Medicine and Cell Biology, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908

Received 19 December 2005/ Returned for modification 26 April 2006/ Accepted 1 August 2006

The homeodomain (HD) transcription factors are a structurally conserved family of proteins that, through networks of interactions with other nuclear proteins, control patterns of gene expression during development. For example, the network interactions of the pituitary-specific HD protein Pit-1 control the development of anterior pituitary cells and regulate the expression of the hormone products in the adult cells. Inactivating mutations in Pit-1 disrupt these processes, giving rise to the syndrome of combined pituitary hormone deficiency. Pit-1 interacts with CCAAT/enhancer-binding protein alpha (C/EBP{alpha}) to regulate prolactin transcription. Here, we used the combination of biochemical analysis and live-cell microscopy to show that two different point mutations in Pit-1, which disrupted distinct activities, affected the dynamic interactions between Pit-1 and C/EBP{alpha} in different ways. The results showed that the first {alpha}-helix of the POU-S domain is critical for the assembly of Pit-1 with C/EBP{alpha}, and they showed that DNA-binding activity conferred by the HD is critical for the final intranuclear positioning of the metastable complex. This likely reflects more general mechanisms that govern cell-type-specific transcriptional control, and the results from the analysis of the point mutations could indicate an important link between the mislocalization of transcriptional complexes and disease processes.

* Corresponding author. Mailing address: Department of Medicine, Box 800578 HSC, University of Virginia Health Services, Charlottesville, VA 22908-0578. Phone: (434) 982-3623. Fax: (434) 982-0088. E-mail: rnd2v{at}virginia.edu.

{triangledown} Published ahead of print on 14 August 2006.

{dagger} Present address: Laboratory of Receptor Biology and Gene Expression, Bldg. 41, Room B602, National Cancer Institute, NIH, Bethesda, MD 20892-5055.

Molecular and Cellular Biology, November 2006, p. 8087-8098, Vol. 26, No. 21
0270-7306/06/$08.00+0     doi:10.1128/MCB.02410-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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