Modulation of Growth Factor/Cytokine Synthesis and Signaling by 1α,25-Dihydroxyvitamin D3: Implications in Cell Growth and Differentiation

Gürlek, Alper; Pittelkow, Mark R.; Kumar, Rajiv

doi:10.1210/er.2001-0044

Cited by 149 publications

(116 citation statements)

References 324 publications

(159 reference statements)

Supporting

Mentioning

107

Contrasting

Unclassified

Order By: Relevance

“…It inhibits dendritic cell differentiation from peripheral blood monocytes and suppresses the production of IL-12, a cytokine crucial for the development of Th1 cells (1,7,33,34). Consistent with its anti-inflammatory role, 1,25(OH) 2 D 3 downregulates the expression of many other proinflammatory cytokines such as IL-1, IL-6, IL-8, and TNF-␣ in a variety of cell types (9,12).…”

mentioning

confidence: 94%

Increased NF-κB activity in fibroblasts lacking the vitamin D receptor

Sun

Kong

Duan³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

215

194

View full text Add to dashboard Cite

1,25-Dihydroxyvitamin D [1,25(OH)2D3] is known to have anti-inflammatory activity; however, the molecular mechanism remains poorly defined. Here we show that the nuclear vitamin D receptor (VDR) is directly involved in the regulation of NF-κB activation, a pathway essential for inflammatory response. In mouse embryonic fibroblasts (MEFs) derived from VDR−/− mice, the basal level of κB inhibitor (IκB) α protein was markedly decreased compared with VDR+/− MEFs; however, degradation of IκBα and its phosphorylation in response to TNF-α treatment or Salmonella infection were not altered in VDR−/− cells, neither were the levels of IκB kinase-α and IκB kinase-β proteins. Consistent with IκBα reduction, p65 accumulation in the nucleus was markedly increased in unstimulated VDR−/− cells. In addition, the physical interaction between VDR and p65 was absent in VDR−/− MEFs, which may free p65 and increase its activity. Consequently, these alterations combined led to a marked increase in nuclear p65 DNA binding and NF-κB transcriptional activity; consistently, induction of IL-6 by TNF-α or IL-1β was much more robust in VDR−/− than in VDR+/− cells, indicating that VDR−/− cells are more susceptible to inflammatory stimulation. Therefore, cells lacking VDR appear to be more proinflammatory due to the intrinsic high NF-κB activity. The reduction of IκBα in VDR−/− MEFs may be partially explained by the lack of VDR-mediated stabilization of IκBα by 1,25(OH)2D3. This is supported by the observation that IκBα degradation induced by TNF-α was inhibited by 1,25(OH)2D3 in VDR+/− cells, but not in VDR−/− cells. Taken together, these data suggest that VDR plays an inhibitory role in the regulation of NF-κB activation.

show abstract

mentioning

confidence: 94%

Increased NF-κB activity in fibroblasts lacking the vitamin D receptor

Sun

Kong

Duan³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

215

194

View full text Add to dashboard Cite

show abstract

“…Although initially identified as a regulator of calcium homeostasis, vitamin D is now known to have a broad spectrum of actions, driven by the virtually ubiquitous expression of the vitamin D receptor (VDR), a nuclear receptor and hormone-regulated transcription factor. For example, it acts as a chemopreventive agent in several animal models of cancer and induces cell-cycle arrest and nonmalignant and malignant cell differentiation (5)(6)(7)(8)(9)(10)(11). Epidemiological data have provided associations between lack of UV-B exposure, vitamin D insufficiency, and the prevalence of certain cancers (12).…”

mentioning

confidence: 99%

Vitamin D receptor as a master regulator of the c-MYC/MXD1 network

Salehi-Tabar¹,

Nguyen-Yamamoto²,

Tavera-Mendoza³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

113

View full text Add to dashboard Cite

Vitamin D signaling regulates cell proliferation and differentiation, and epidemiological data suggest that it functions as a cancer chemopreventive agent, although the underlying mechanisms are poorly understood. Vitamin D signaling can suppress expression of genes regulated by c-MYC, a transcription factor that controls epidermal differentiation and cell proliferation and whose activity is frequently elevated in cancer. We show through cell-and animal-based studies and mathematical modeling that hormonal 1,25-dihydroxyvitamin D (1,25D) and the vitamin D receptor (VDR) profoundly alter, through multiple mechanisms, the balance in function of c-MYC and its antagonist the transcriptional repressor MAD1/MXD1. 1,25D inhibited transcription of c-MYC-regulated genes in vitro, and topical 1,25D suppressed expression of c-MYC and its target setd8 in mouse skin, whereas MXD1 levels increased. 1,25D inhibited MYC gene expression and accelerated its protein turnover. In contrast, it enhanced MXD1 expression and stability, dramatically altering ratios of DNA-bound c-MYC and MXD1. Remarkably, F-box protein FBW7, an E3-ubiquitin ligase, controlled stability of both arms of the c-MYC/MXD1 push-pull network, and FBW7 ablation attenuated 1,25D regulation of c-MYC and MXD1 turnover. Additionally, c-MYC expression increased upon VDR knockdown, an effect abrogated by ablation of MYC regulator β-catenin. c-MYC levels were widely elevated in vdr −/− mice, including in intestinal epithelium, where hyperproliferation has been reported, and in skin epithelia, where phenotypes of VDR-deficient mice and those overexpressing epidermal c-MYC are similar. Thus, 1,25D and the VDR regulate the c-MYC/MXD1 network to suppress c-MYC function, providing a molecular basis for cancer preventive actions of vitamin D.V itamin D is obtained naturally from limited dietary sources. It is also generated by cutaneous conversion of 7-dehydrocholesterol in the presence of adequate surface solar UV-B radiation, which varies with latitude and time of year (1). Vitamin D has attracted broad clinical interest because insufficiency or deficiency is widespread in several populations worldwide (2-4). Although initially identified as a regulator of calcium homeostasis, vitamin D is now known to have a broad spectrum of actions, driven by the virtually ubiquitous expression of the vitamin D receptor (VDR), a nuclear receptor and hormone-regulated transcription factor. For example, it acts as a chemopreventive agent in several animal models of cancer and induces cell-cycle arrest and nonmalignant and malignant cell differentiation (5-11). Epidemiological data have provided associations between lack of UV-B exposure, vitamin D insufficiency, and the prevalence of certain cancers (12). A large prospective study associated vitamin D sufficiency with reduced total cancer incidence and mortality, particularly in digestive cancers [head and neck squamous cell carcinoma (HNSCC), esophageal, pancreatic, stomach, and colorectal cancers] and leukemias (13). VDR gene polymorphi...

show abstract

“…Progression of differentiation along the osteogenic lineage requires the complex genetic and biochemical interplay of gene regulatory signaling pathways involving several key transcription factors and distinct growth factor-dependent kinase cascades (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). Molecular mechanisms that regulate expression of the osteoblast phenotype have been defined in considerable detail, although the principal signaling cascades that control osteoblast proliferation remain to be comprehensively characterized.…”

mentioning

confidence: 99%