Mechanisms of Nkx6.1 governing β cell development and function

2006 2006

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Abstract (summary)

The NK homeobox transcription factor Nkx6.1 is a critical regulator of the final stages of β cell differentiation within the developing pancreas. However, very little is known as to how Nkx6.1 directs the phenotypic development of the β cell or if Nkx6.1 has a role in the mature, insulin-secreting β cell. Here we elucidate the role of Nkx6.1 by identifying and characterizing three of its native downstream gene targets: the glucagon, insulin , and nkx6.1 genes. Whereas Nkx6.1 appears to act as a repressor of transcription at the glucagon and insulin promoters (a property mapped to its N terminus), Nkx6.1 functions to enhance the transcription of its own gene, perhaps accounting for its persistent expression within the mature β cell. This transcriptional activation function was mapped to the C terminus of the protein, a region previously suggested to modulate its DNA binding affinity. Interestingly, the repression-versus-activation functions of Nkx6.1 appear to rely at least in part on differential sequence recognition at target promoters. While Nkx6.1 represses transcription through association with conserved TAAT elements, Nkx6.1 activates transcription by binding a non-consensus ATTT element. In an attempt to understand the mechanism by which the C terminus of Nkx6.1 modulates the protein's recognition or affinity for such sequences, we performed numerous biochemical and structural analyses of the protein. Surprisingly, a negatively charged region of the Nkx6.1 C terminus selectively enhances its DNA binding affinity for TAAT-containing DNA sequences, a property that is not attributable to significant structural alterations in the protein in the absence of DNA. Taken together, these data provide a framework by which we can systematically dissect the broad mechanistic role of Nkx6.1 as it relates to β cell development and function.

Indexing (details)

0419: Pharmacology
Identifier / keyword
Health and environmental sciences; Beta-cells; Insulin; Nkx6.1
Mechanisms of Nkx6.1 governing β cell development and function
Taylor, David G., Jr.
Number of pages
Publication year
Degree date
School code
DAI-B 66/12, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
054244335X, 9780542443350
Mirmira, Raghavendra
University of Virginia
University location
United States -- Virginia
Source type
Dissertations & Theses
Document type
Dissertation/thesis number
ProQuest document ID
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
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