Regulation of Human Epidermal Keratinocyte Differentiation by the Vitamin D Receptor and its Coactivators DRIP205, SRC2, and SRC3

Hawker, Nathaniel P.; Pennypacker, Sally D.; Chang, Sam K. C.; Bikle, Daniel D.

doi:10.1038/sj.jid.5700624

Cited by 81 publications

(62 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Apart from exerting its classical functions, vitamin D receptor has been shown to exert antiproliferative actions in several different cancer cell lines (24,25). Recently, VDR has been implicated to play a broader role in the differentiation of epithelial keratinocytes and immunomodulatory activities (26,27). Although extensive work has been performed on the biological function of vitamin D and its analogs, little is known about the transcriptional regulation of VDR.…”

mentioning

confidence: 99%

Differential Regulation of Vitamin D Receptor (VDR) by the p53 Family

Kommagani

Payal

Kadakia

2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

p63 and p73, members of the p53 family, have been shown to be functionally distinct from p53. Vitamin D receptor (VDR) is a ligand (vitamin D 3 )-dependent transcription factor, which is shown to play a major role in calcium homeostasis and keratinocyte differentiation. Vitamin D and its analogues in combination with DNA-damaging agents are extensively used for cancer chemotherapy. In this report, we examined whether p53 affects p63-mediated induction of VDR and studied the effect of DNA damage on VDR induction in p53 null cell lines. Our results demonstrate that p53 itself does not induce VDR expression, nor does it affect p63-mediated VDR induction in the cell lines tested in this study. Furthermore, we observed p53-independent activation of VDR upon DNA damage and associated the induction of VDR to p73. We have demonstrated that ectopic expression of various p73 isoforms can induce VDR expression. Inhibition of p73 in cells treated with DNA-damaging agents exhibited decreased VDR expression. Finally, we show that upon DNA damage, induction of VDR sensitizes the cells to vitamin D treatment. In conclusion, our results indicate that VDR is regulated by p63 and p73 and that the induction of VDR expression upon DNA damage is p73-dependent. p53, the most frequently altered gene in human cancers, controls multiple signaling pathways by regulating the genes involved in cell cycle arrest, apoptosis, DNA repair, cellular senescence, and inhibition of angiogenesis (1). Stabilization of p53 protein occurs in response to various stress stimuli including DNA damage, viral infection, or oncogenic activation (1, 2). Although the functional significance of p53 and its interacting proteins have been studied extensively, it was not until 1997 that the functional homologues of p53, namely p63 and p73, were discovered. Despite being structurally similar to p53, p63 and p73 were shown to be functionally more diverse and distinct from p53 (3, 4). p63 knock-out mice were born with severe developmental defects, which included lack of skin and various epithelial tissues, whereas p73 knock-out mice were born with neuronal defects as well as changes in sexual behavior (5, 6).Functional diversities associated with p63 and p73 are partly due to their ability to generate multiple transcripts. Differential promoter usage by both p63 and p73 results in the generation of either transactivation domain containing isoforms (TAp63 and TAp73) or NH 2 -terminally truncated isoforms (⌬Np63 and ⌬Np73) (7). Additionally, multiple carboxyl termini variants, ␣, ␤, and ␥ of p63 and ␣, ␤, ␥, ⑀, and ␦ of p73, are generated due to the differential splicing of COOH terminus. Due to their structural similarity with p53, TA isoforms of both p63 and p73 have been shown to activate various p53-responsive genes and promote cell cycle arrest and apoptosis (8, 9). On the contrary, elevated levels of ⌬Np63 and ⌬Np73 isoforms have been reported in several human cancers, and these isoforms have also been associated with the induction of various genes involved in prom...

show abstract

mentioning

confidence: 99%

Differential Regulation of Vitamin D Receptor (VDR) by the p53 Family

Kommagani

Payal

Kadakia

2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…The phosphatidylinositol 3-kinase (PI3-K)/Akt signaling has been implicated in 1,25(OH) 2 D 3 -induced differentiation of THP-1 human leukemia cells [62,89], HL60 cells [70,89e92] and keratinocytes, in which the membrane receptor for 1,25(OH) 2 D 3 is reported to be annexin II [67]. While in several studies [70,92] 1,25(OH) 2 D 3 was found to [412,413] Loricrin Late differentiation marker [409,410] Filaggrin Late differentiation marker [409,410] Cornified envelope formation [407,414] MUSCLE CELLS (C2C12) [93]. Likewise, vitamin D analogs downregulated Akt in SCC cells [94] and ErbB2 overexpressing mammary tumors [95], which was associated, respectively, with the anti-proliferative effect and inhibition of tumor growth.…”

Section: Phosphatidylinositol 3-kinase/akt Pathwaymentioning

confidence: 98%

Vitamin D Effects on Differentiation and Cell Cycle

2011

View full text Add to dashboard Cite

“…1,25(OH) 2 D 3 is involved in all steps of this process in that it limits proliferation in the basal layer while inducing in a sequential pattern the expression of genes whose products ultimately produce the permeability barrier. The ability of 1,25(OH) 2 D to act sequentially on gene expression as the differentiation process unfolds is due to the differential distribution of coactivators (DRIP205 and SRC3) within the epidermis as a function of differentiation [87] and the differential utilization of these coactivators by genes involved in the early and late stages of differentiation [88]. CYP27b1 like VDR is found throughout the epidermis, although expression appears to be higher in the basal layer of the epidermis [19,28,29].…”

Section: Function Of Extra Renal Cyp27b1mentioning

confidence: 99%

Extra Renal Synthesis of 1,25-dihydroxyvitamin D and its Health Implications

Bikle

2009

Clinic Rev Bone Miner Metab

Self Cite

View full text Add to dashboard Cite

Although the kidney was initially thought to be the sole organ responsible for the production of 1,25(OH) 2 D 3 via its enzyme CYP27b1, it is now appreciated that the expression of CYP27b1 in tissues other than the kidney is wide spread. However, the kidney is the major source for circulating 1,25(OH) 2 D 3 . Therefore the existence of the capacity for extra renal 1,25(OH) 2 D 3 production begs the question why, and in particular whether the extra renal production of 1,25(OH) 2 D 3 has physiologic importance. In this chapter this question will be discussed. First a compilation of the extra renal sites for CYP27b1 expression is provided. This is followed by a discussion of the regulation of CYP27b1 expression and activity in extra renal tissues, pointing out that such regulation is tissue specific and different from that of CYP27b1 in the kidney. Finally the physiologic significance of extra renal 1,25(OH) 2 D 3 production is examined, with special focus on the role of CYP27b1 in regulation of cellular proliferation and differentiation, hormone secretion, and immune function. At this point the data do not clearly demonstrate an essential role for CYP27b1 expression in any tissue outside the kidney, but several examples pointing in this direction are provided. With the availability of the mouse enabling tissue-specific deletion of CYP27b1, the role of extra renal CYP27b1 expression can now be addressed definitively.

show abstract

Regulation of Human Epidermal Keratinocyte Differentiation by the Vitamin D Receptor and its Coactivators DRIP205, SRC2, and SRC3

Cited by 81 publications

References 14 publications

Differential Regulation of Vitamin D Receptor (VDR) by the p53 Family

Differential Regulation of Vitamin D Receptor (VDR) by the p53 Family

Vitamin D Effects on Differentiation and Cell Cycle

Extra Renal Synthesis of 1,25-dihydroxyvitamin D and its Health Implications

Contact Info

Product

Resources

About