RXRα Ablation in Epidermal Keratinocytes Enhances UVR-Induced DNA Damage, Apoptosis, and Proliferation of Keratinocytes and Melanocytes

Wang, Zhixing; Coleman, Daniel J.; Bajaj, Gaurav; Liang, Xiaofeng; Ganguli‐Indra, Gitali; Indra, Arup K.

doi:10.1038/jid.2010.290

Cited by 41 publications

(65 citation statements)

References 69 publications

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“…9-cis-RA inhibits activation-induced apoptosis in T-cell hybridomas and thymocytes by blocking the expression of Fas ligand following activation. RXRα has a protective role in cellular apoptosis of keratinocytes and melanocytes [60] , and RXRα antagonist HX531 inhibits the apoptotic effect of 4-para-Nonylphenol in mouse embryonic neuronal cells through an RXR-mediated mitochondria-dependent signaling pathway [61] . Activation of RXRα induces apoptosis in NB4 acute promyelocytic leukemia cells [3] .…”

Section: Nongenomic Activity Of Rxr and Apoptosismentioning

confidence: 99%

Regulation of the nongenomic actions of retinoid X receptor-α by targeting the coregulator-binding sites

Zhang

Chen

et al. 2014

Acta Pharmacol Sin

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Retinoid X receptor-α (RXRα), a unique member of the nuclear receptor superfamily, represents an intriguing and unusual target for pharmacologic interventions and therapeutic applications in cancer, metabolic disorders and neurodegenerative diseases. Despite the fact that the RXR-based drug Targretin (bexarotene) is currently used for treating human cutaneous T-cell lymphoma and the fact that RXRα ligands (rexinoids) show beneficial effects in the treatment of cancer and diseases, the therapeutic potential of RXRα remains unexplored. In addition to its conventional transcription regulation activity in the nucleus, RXRα can act in the cytoplasm to modulate important biological processes, such as mitochondria-dependent apoptosis, inflammation, and phosphatidylinositol 3-kinase (PI3K)/ AKT-mediated cell survival. Recently, new small-molecule-binding sites on the surface of RXRα have been identified, which mediate the regulation of the nongenomic actions of RXRα by a class of small molecules derived from the nonsteroidal anti-inflammatory drug (NSAID) Sulindac. This review discusses the emerging roles of the nongenomic actions of RXRα in the RXRα signaling network, and their possible implications in cancer, metabolic and neurodegenerative disorders, as well as our current understanding of RXRα regulation by targeting alternate binding sites on its surface.

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Section: Nongenomic Activity Of Rxr and Apoptosismentioning

confidence: 99%

Regulation of the nongenomic actions of retinoid X receptor-α by targeting the coregulator-binding sites

Zhang

Chen

et al. 2014

Acta Pharmacol Sin

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“…[4][5][6][7][8]11 with the activating NRAS mutation in the melanocytes, represent a metastatic melanoma model…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

“…[4,5] However, newer emerging genetic targets include Neuroblastoma -Rat Sarcoma (NRAS) [4][5][6] and nuclear receptors like Retinoid X Receptor-α (RXRα) genes. [7,8] In pathological conditions, point mutations at the codon 61 of NRAS (NRASQ 61K ) gene locks the activated form of NRAS-GTP thereby promoting continuous up regulation of downstream effector proteins and signaling pathways in the malignant melanoma phenotype. [9,10] Activated NRAS Q61K mutations play a significant role in the development of metastatic melanoma and are the primary driver mutations that are responsible for the spread of the disease in humans.…”

Section: Introductionmentioning

confidence: 99%

A three-drug nanoscale drug delivery system designed for preferential lymphatic uptake for the treatment of metastatic melanoma

Doddapaneni

Kyryachenko

Chagani

et al. 2015

Journal of Controlled Release

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Metastatic Melanoma has a high mortality rate due to lymphatic progression of the disease. Current treatment is surgery followed by radiation and intravenous chemotherapy. However, drawbacks for current chemotherapeutics lie in the fact that they develop resistance and do not achieve therapeutic concentrations in the lymphatic system. We hypothesize that a three-drug nanoscale drug delivery system, tailored for lymphatic uptake, administered subcutaneously, will have decreased drug resistance and therefore offer better therapeutic outcomes. We prepared and characterized nanoparticles (NP) with docetaxel, everolimus, and LY294002 in polyethyleneglycol-block-poly(ε-caprolactone) (PEG-PCL) polymer with different charge distributions by modifying the ratio of anionic and neutral end groups on the PEG block. These NP are similarly sized (~ 48nm), with neutral, partially charged, or fully charged surface. The NP are able to load ~ 2mg/mL of each drug and are stable for 24 h. The NP are assessed for safety and efficacy in two transgenic metastatic melanoma mouse models. All the NP were safe in both models based on general appearance, weight changes, death, and blood biochemical analyses. The partially charged NP are most effective in decreasing the number of melanocytes at both the proximal (sentinel) lymph node (LN) and the distal LN from the injection site. The neutral NP are efficacious at the proximal LN, while the fully charged NP have no effect on either LN. Thus, our data indicates that the NP surface charge and lymphatic efficacy are closely tied to each other and the partially charged NP have the highest potential in treating metastatic melanoma. GRAPHICAL ABSTRACT

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“…Thus, paracrine and autocrine molecules secreted by keratinocytes, fibroblast and melanocytes are necessary for the regulation of pigment production in response to environmental factors and also to control topological differences in the skin color [88,92]. In addition, these factors influence not only the growth and pigmentation of melanocytes, but also their shape, dendricity, mobility and adhesive properties [50,93].…”

Section: Melanocytes In the Epidermismentioning

confidence: 99%

Heterogeneity of neural crest-derived melanocytes

2013

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The majority of melanocytes originate from the neural crest cells (NCC) that migrate, spread on the whole embryo’s body to form elements of the nervous system and skeleton, endocrinal glands, muscles and melanocytes. Human melanocytes differentiate mainly from the cranial and trunk NCC. Although melanocyte development has traditionally been associated with the dorsally migrating trunk NCC, there is evidence that a part of melanocytes arise from cells migrating ventrally. The ventral NCC differentiate into neurons and glia of the ganglia or Schwann cells. It has been suggested that the precursors for Schwann cells differentiate into melanocytes. As melanoblasts travel through the dermis, they multiply, follow the process of differentiation and invade the forming human fetal epidermis up to third month. After birth, melanocytes lose the ability to proliferate, except the hair melanocytes that renew during the hair cycle. The localization of neural crest-derived melanocytes in non-cutaneous places e.g. eye (the choroid and stroma of the iris and the ciliary body), ear (cells of the vestibular organ, cochlear stria vascularis), meninges of the brain, heart seems to indicate that repertoire of melanocyte functions is much wider than we expected e.g. the protection of tissues from potentially harmful factors (e.g. free radicals, binding toxins), storage ions, and anti-inflammatory action.

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RXRα Ablation in Epidermal Keratinocytes Enhances UVR-Induced DNA Damage, Apoptosis, and Proliferation of Keratinocytes and Melanocytes

Cited by 41 publications

References 69 publications

Regulation of the nongenomic actions of retinoid X receptor-α by targeting the coregulator-binding sites

Regulation of the nongenomic actions of retinoid X receptor-α by targeting the coregulator-binding sites

A three-drug nanoscale drug delivery system designed for preferential lymphatic uptake for the treatment of metastatic melanoma

Heterogeneity of neural crest-derived melanocytes

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