Gene targeting by the vitamin D response element binding protein reveals a role for vitamin D in osteoblast mTOR signaling.
نویسندگان
چکیده
Transcriptional regulation by hormonal 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] involves occupancy of vitamin D response elements (VDREs) by the VDRE binding protein (VDRE-BP) or 1,25(OH)(2)D(3)-bound vitamin D receptor (VDR). This relationship is disrupted by elevated VDRE-BP, causing a form of hereditary vitamin D-resistant rickets (HVDRR). DNA array analysis showed that of 114 genes regulated by 1,25(OH)(2)D(3) in control cells, almost all (113) were rendered insensitive to the hormone in VDRE-BP-overexpressing HVDRR cells. Among these was the gene for DNA-damage-inducible transcript 4 (DDIT4), an inhibitor of mammalian target of rapamycin (mTOR) signaling. Chromatin immunoprecipitation PCR using 1,25(OH)(2)D(3)-treated osteoblasts confirmed that VDR and VDRE-BP compete for binding to the DDIT4 gene promoter. Expression of DDIT4 mRNA in these cells was induced (1.6-6 fold) by 1,25(OH)(2)D(3) (10-100 nM), and Western blot and flow cytometry analysis showed that this response involved suppression of phosphorylated S6K1(T389) (a downstream target of mTOR) similar to rapamycin treatment. siRNA knockdown of DDIT4 completely abrogated antiproliferative responses to 1,25(OH)(2)D(3), whereas overexpression of VDRE-BP exerted a dominant-negative effect on transcription of 1,25(OH)(2)D(3)-target genes. DDIT4, an inhibitor of mTOR signaling, is a direct target for 1,25(OH)(2)D(3) and VDRE-BP, and functions to suppress cell proliferation in response to vitamin D.
منابع مشابه
Vitamin D and the urgency of paying attention to this vital element in the body
Vitamin D is a vital element in the body that plays an important role in the growth and strength of muscles and bones by its effect on calcium absorption from the intestine. Vitamin D biosynthesis begins with the exposure to UV of sunlight from the skin. Cholecalciferol transfers from the skin and the intestine to the liver, and then binds to the DBP protein and eventually enters the kidney to...
متن کاملKlotho Protein,A Biomarker for AKI
Klotho is an anti-aging single-pass membrane protein that is mainly produced in the kidney. The level of soluble klotho decreases with age and the klotho gene is associated with an increased risk of age-related diseases, such as diabetes, skin atrophy, chronic kidney disease, ataxia and cancer. The klotho gene is composed of five exons and encodes a membrane glycoprotein located in the plasma ...
متن کاملEffect of vitamin D supplementation on CREB-TrkB-BDNF pathway in the hippocampus of diabetic rats
Objective(s): Cyclic AMP (adenosine monophosphate) response element-binding protein (CREB) and Brain-derived neurotrophic factor (BDNF) are reported to broadly involve in learning capacity and memory. BDNF exerts its functions via tropomyosin receptor kinase B (TrkB). BDNF transcription is regulated by stimulating CREB phosphorylation. The CREB-TrkB-BDNF pathway is rep...
متن کاملThe role of polymorphism of TaqI in Vitamin D receptor gene and risk of ovarian cancer in women of North India
Background & objective: Ovarian cancer mortality is associated with lower regional sunlight exposure. Vitamin D and its metabolites are best known for their action in calcium and bone metabolism. However, epidemiological studies have suggested that an increased ovarian cancer risk is associated with decreased production of vitamin D. The vitamin D signaling pathway is involved in a wide variety...
متن کاملP 80: Effects of Vitamin D on Migraine
Migraine is a disabling headache disorder. That is characterized by recurrent unilateral pulsatile headaches. It is one of the most common neurological disorder in the world that nearly one billion of people are affected by migraines. The main Migraine’s features are headaches. Accompanying symptoms are nausea, sometimes vomiting, photophobia, neck pain and muscle tension. Its attacks las...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- FASEB journal : official publication of the Federation of American Societies for Experimental Biology
دوره 25 3 شماره
صفحات -
تاریخ انتشار 2011