Identification of vitamin D receptor as a target of p63

Kommagani, Ramakrishna; Caserta, Tina M.; Kadakia, Madhavi

doi:10.1038/sj.onc.1209412

Cited by 47 publications

(46 citation statements)

References 46 publications

(52 reference statements)

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“…p14 ARF was also shown to negatively regulate the transcriptional activity of p63 (31). We have recently shown that p14 ARF inhibits TAp63g-mediated induction of vitamin D receptor (13). Here, we examined whether p14 ARF affected TAp63g-mediated induction of Shh expression.…”

Section: Tap63c (R279h) Mutant Fails To Transactivate Shh Expressionmentioning

confidence: 99%

“…TAp63g has also been shown to activate the expression of Jagged 1 and Jagged 2, which are involved in Notch signaling, whereas Notch 1 activation has also been shown to suppress DNp63a expression, demonstrating a cross-talk between these pathways (7,8). Additional studies have shown that the biological effects of p63 in development and tumor suppression is exerted through the regulation of multiple signaling pathways (9)(10)(11)(12)(13)(14)(15)(16)(17). p73, another member of the p53 family, was also discovered based on structural similarities to p53 (18).…”

Section: Introductionmentioning

confidence: 99%

“…The ChIP assay was done using the ChIP kit and the manufacturer's recommended protocol (Active Motif, Carlsbad, CA) and done as previously described (13). PCR amplification of Shh promoter regions (sites 1-5) shown in Fig.…”

Section: Chip Assaymentioning

confidence: 99%

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p63 Overexpression Induces the Expression of Sonic Hedgehog

Caserta

Kommagani²,

Yuan

et al. 2006

Molecular Cancer Research

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p63 and p73 are members of the p53 protein family and have been shown to play an important role in cell death, development, and tumorigenesis. In particular, p63 has been shown to be involved in the maintenance of epidermal stem cells and in the stratification of the epidermis. Sonic Hedgehog (Shh) is a morphogen that has also been implicated to play a role in epithelial stem cell proliferation and in the development of organs. Recently, Shh has also been shown to play an important role in the progression of a variety of cancers. In this report, we show that p63 and p73 but not p53 overexpression induces Shh expression. In particular, p63; and p63B (both TA and #N isoforms) and TAp73B isoform induce Shh. Expression of Shh was found to be significantly reduced in mouse embryo fibroblasts obtained from p63À/À mice. The naturally occurring p63 mutant TAp63;(R279H) and the tumor suppressor protein p14 ARF inhibited the TAp63;-mediated transactivation of Shh. The region À228 to À102 bp of Shh promoter was found to be responsive to TAp63;-induced transactivation and TAp63; binds to regions within the Shh promoter in vivo.

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Section: Tap63c (R279h) Mutant Fails To Transactivate Shh Expressionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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p63 Overexpression Induces the Expression of Sonic Hedgehog

Caserta

Kommagani²,

Yuan

et al. 2006

Molecular Cancer Research

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“…Expression plasmids encoding TAp63␥, TAp73␤, ⌬Np73␤, and TAp73␣ were constructed in cytomegalovirus-driven pcDNA3.1A vector as described earlier (28). VDR full-length and minimal promoter luciferase constructs were constructed as described previously (29). p53 expression plasmid was a generous gift from Dr. Steven Berberich (Wright State University).…”

Section: Methodsmentioning

confidence: 99%

“…Quantitative real time PCR analysis was performed in a 96-well microtiter plate format on an ABI Prism7900HT sequence detection system using TaqMan Universal master mix and Assays on Demand specific for VDR (Hs_0017213_m1), p21 (Hs_00355782_m1), p73 (Hs_00232088_m1), and CYP27B1 ((Hs_00168017_m1) (PerkinElmer Life Sciences). Relative mRNA quantitation was performed by using the comparative ⌬⌬Ct method as described earlier (28,29).…”

Section: Methodsmentioning

confidence: 99%

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

Kommagani

Payal

Kadakia

2007

Journal of Biological Chemistry

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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...

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Mammary epithelial cell transformation is associated with deregulation of the vitamin D pathway

Kemmis

Welsh

2008

J of Cellular Biochemistry

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The vitamin D endocrine system mediates anti-proliferative and pro-differentiating signaling in multiple epithelial tissues, including mammary gland and breast tumors. The vitamin D metabolite 1α,25(OH) 2 D 3 mediates growth inhibitory signaling via activation of the vitamin D receptor (VDR), a ligand dependent transcription factor. 1α,25(OH) 2 D 3 is synthesized from 25(OH)D 3 (the major circulating form of the vitamin) by the mitochondrial enzyme CYP27b1 in renal and other tissues. Human mammary epithelial (HME) cells express VDR and CYP27b1 and undergo growth inhibition when exposed to physiological concentrations of 25(OH)D 3 , suggesting that autocrine or paracrine vitamin D signaling contributes to maintenance of differentiation and quiescence in the mammary epithelium. In the current studies we tested the hypothesis that cancer cells would exhibit reduced sensitivity to vitamin D mediated negative growth regulation. We used a series of progressively transformed HME cell lines expressing known oncogenic manipulations to study the effects of transformation per se on the vitamin D pathway. We report that mRNA and protein levels of VDR and CYP27b1 were reduced greater than 70% upon stable introduction of known oncogenes (SV40 T antigens and H-rasV12) into HME cells. Oncogenic transformation was also associated with reduced 1α,25(OH) 2 D 3 synthesis, and cellular sensitivity to growth inhibition by 1α,25(OH) 2 D 3 and 25(OH)D 3 was decreased approximately 100-fold in transformed cells. These studies provide evidence that disruption of the vitamin D signaling pathway occurs early in the cancer development process.

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Identification of vitamin D receptor as a target of p63

Cited by 47 publications

References 46 publications

p63 Overexpression Induces the Expression of Sonic Hedgehog

p63 Overexpression Induces the Expression of Sonic Hedgehog

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

Mammary epithelial cell transformation is associated with deregulation of the vitamin D pathway

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