UCSF DIABETES, ENDOCRINOLOGY & METABOLISM TRAINING PROGRAM FACULTY RESEARCH SUMMARIES

Regulation of Intestinal Calcium Transport by Vitamin D

We are currently focused on the mechanisms by which 1,25(OH) 2 D regulates the flow of calcium across the intestinal brush border. We are evaluating the interacting roles of the newly discovered TRPV6 (a vitamin D-regulated calcium channel specific for the brush border), calmodulin (CaM) (the major calcium binding protein in the brush border), and myosin 1 (a single headed myosin unique to the brush border which uses CaM as its light chain) in this process. We are using a cell culture model (Caco2 cells) as well as mice null for TRPV6, myosin1, the vitamin D receptor, and the 25OHD 1a-hydroxylase for these studies.

Effect of Skeletal Unloading on Bone Formation

The fundamental observation that we are trying to understand is why skeletal unloading leads to a cessation of bone formation. We are trying to understand the signals by which this takes place. Skeletal unloading results in resistance to the anabolic actions of IGF-I. This resistance is due to a failure of IGF-I to activate its receptor in the osteoblasts from unloaded bone. Integrins are part of this mechanism in that integrin expression is reduced in cells from unloaded bone and blocking integrin function duplicates the resistance to IGF-I seen in unloaded bone. The mechanism(s) underlying the role of integrins in IGF-I activation of its receptor is being investigated. We have also been studying IGF-I and IGF-I receptor null mice and determined that such mice are resistant to the anabolic actions of parathyroid hormone. In more recent studies with these mice, we have discovered that IGF-I is essential for normal osteoclast development as well as osteoblast differentiation.

Regulation of Keratinocyte Differentiation by Calcium and Vitamin D

We made the initial discovery that keratinocytes are prodigious producers not only of vitamin D but also its active metabolite 1,25(OH) 2 D. Our recent efforts have been directed toward understanding the mechanisms by which 1,25(OH) 2 D and calcium regulate differentiation of these cells. In the course of these investigations, we discovered the central importance of the calcium receptor and PLC-?1 in the differentiation process and determined their regulation by 1,25(OH) 2 D and calcium. Furthermore, we have extensively studied the involucrin gene, which encodes a critical component of the cornified envelope, and discovered a region in its promoter that confers both calcium and 1,25(OH) 2 D responsiveness. We have gained insight into the ability of 1,25(OH) 2 D to induce sequentially the genes required for differentiation of keratinocytes (and the failure of same in squamous cell carcinoma) by showing that the vitamin D receptor changes its binding to coactivator complexes from DRIP to SRC during the differentiation process and that the vitamin D response elements in the genes required for differentiation prefer the VDR/SRC complex for their induction. The shift from DRIP to SRC binding does not occur in squamous cell carcinoma in that DRIP 205 is overexpressed, blocking the transition to SRC coactivation, and so blocking the induction of genes required for differentiation.

Selected References

Sakata T, Wang Y, Halloran BP, Elalieh HZ, Cao J, Bikle DD 2004. Skeletal unloading induces resistance to IGF-I by inhibiting activation of the IGF-I signaling pathways. J Bone Min Res 19:436-446.

Bikle DD, Chang S, Crumrine D, Elalieh H, Man M-Q, Choi EH, Dardenne O, Xie Z, St. Arnaud R, Feingold K, Elias PM. 2004 25 Hydroxyvitamin D 1 alpha-hydroxylase is required for optimal epidermal differentiation and permeability barrier homeostasis. J Invest Dermatol 122:984-992.

Xie A, Singleton PA, Bourguignon LYW, Bikle DD. 2005. Calcium-induced human keratinocyte differentiation requires src- and fyn-mediated phosphatidylinositol 3-kinase dependent activation of phospholipase C-gamma 1. Molec Biol Cell 16(7):3236-46.

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