The interaction between Ku antigen and REF1 protein mediates negative gene regulation by extracellular calcium

U Chung1, T Igarashi, T Nishishita

  • 1Fourth Department of Internal Medicine, University of Tokyo School of Medicine, Bunkyo-ku, Tokyo 112, Japan.

Insights

Extracellular calcium (Ca2+e) regulates gene expression via the Ku antigen and REF1 protein. Their specific interaction enables sequence-specific DNA binding, uncovering a novel mechanism for gene regulation.

Area of Science:

  • Molecular Biology
  • Gene Regulation
  • Biochemistry

Background:

  • Extracellular calcium (Ca2+e) negatively regulates genes like the human parathyroid hormone gene through specific DNA-binding proteins.
  • The Ku antigen is known to mediate this Ca2+e-dependent gene regulation by interacting with the REF1 protein.
  • The mechanism behind the Ku antigen's sequence-specific DNA binding has remained unclear.

Purpose of the Study:

  • To elucidate the mechanism by which the Ku antigen achieves sequence-specific DNA binding.
  • To understand the role of the interaction between Ku antigen and REF1 in gene regulation.

Main Methods:

  • Investigated the interaction between the Ku antigen and REF1 protein.
  • Analyzed the DNA-binding properties of the Ku antigen-REF1 complex.

Main Results:

  • Demonstrated that the specific binding of the Ku antigen to REF1 is crucial for its DNA-binding activity.
  • Identified a novel sequence specificity mediated by the Ku antigen-REF1 complex.
  • Showed that this complex formation leads to the regulation of gene expression.

Conclusions:

  • The interaction between Ku antigen and REF1 confers sequence-specific DNA binding to the Ku antigen.
  • This novel mechanism provides new insights into calcium-mediated gene regulation.

Related Concept Videos

Negative Regulator Molecules01:23

Negative Regulator Molecules

Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
Covalently Linked Protein Regulators02:04

Covalently Linked Protein Regulators

Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein.
Receptor Downregulation in MVBs01:15

Receptor Downregulation in MVBs

Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that  lead to cell proliferation, migration, and differentiation. Overexpression of EGFR  stimulates cells to proliferate. Excessive  EGFR activation may...
Regulation of the Unfolded Protein Response01:31

Regulation of the Unfolded Protein Response

Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
Feedback Regulation of Calcium Concentration01:27

Feedback Regulation of Calcium Concentration

Calcium is an essential signaling molecule required for various cellular functions. Calcium pumps and ion channels on cell and organellar membranes, such as those on the endoplasmic reticulum (ER), regulate calcium concentrations inside the cell. They remain closed, keeping the cytosolic calcium levels low at a resting state.
Various transmembrane receptors, such as G protein-coupled receptors (GPCRs), elicit a response to extracellular signals by increasing cytosolic calcium. Activated GPCRs...
Calmodulin-dependent Signaling01:16

Calmodulin-dependent Signaling

Calmodulin (CaM) is a calcium-binding protein in eukaryotes that controls various calcium-regulated cellular processes. It has four calcium-binding sites that bind calcium to form the calcium-calmodulin ( Ca2+-CaM) complex. GPCR stimulation increases the calcium levels in the cells that bind to CaM and induces a conformational change.
The Ca2+-CaM complex does not have enzymatic activity by itself. Instead, the complex binds downstream target proteins, including membrane proteins or enzymes,...