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issn:0022-202
1.  MiTF Regulates Cellular Response to Reactive Oxygen Species through Transcriptional Regulation of APE-1/Ref-1 
Microphthalmia-associated transcription factor (MiTF) is a key transcription factor for melanocyte lineage survival. Most previous work on this gene has been focused on its role in development. A role in carcinogenesis has emerged recently, but the mechanism is unclear. We classified melanoma cells into MiTF-positive and -negative groups and explored the function of MiTF in regulating cellular responses to reactive oxygen species (ROS). The MiTF-positive melanoma cell lines accumulated high levels of apurinic/apyrimidinic endonuclease (APE-1/Ref-1, redox effector-1), a key redox sensor and DNA endonuclease critical for oxidative DNA damage repair. We demonstrate that APE-1 is a transcriptional target for MiTF. Knocking down MiTF led to reduced APE-1 protein accumulation, as well as abolished induction of APE-1 by ROS. MiTF-negative melanoma cells survived more poorly under ROS stress than the MiTF-positive cells based on 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and Trypan blue staining. Overexpression of APE-1 partially rescued ROS-induced cell death when MiTF was depleted. We conclude that MiTF regulates cellular response to ROS by regulation of APE-1, and this may provide a mechanism of how MiTF is involved in melanoma carcinogenesis.
doi:10.1038/jid.2008.255
PMCID: PMC4321967  PMID: 18971960
2.  [No title available] 
PMCID: PMC4101905  PMID: 25029322
3.  [No title available] 
PMCID: PMC4101907  PMID: 25029319
4.  [No title available] 
PMCID: PMC4101909  PMID: 25029321
5.  [No title available] 
PMCID: PMC4101911  PMID: 25029320
6.  [No title available] 
PMCID: PMC4102615  PMID: 24658509
7.  [No title available] 
PMCID: PMC4102619  PMID: 24608988
8.  [No title available] 
PMCID: PMC4102628  PMID: 24608987
9.  [No title available] 
PMCID: PMC4102635  PMID: 24618599
10.  [No title available] 
PMCID: PMC4102636  PMID: 24468745
11.  [No title available] 
PMCID: PMC4102640  PMID: 24594668
12.  [No title available] 
PMCID: PMC4102648  PMID: 24759085
13.  [No title available] 
PMCID: PMC4102657  PMID: 24662766
14.  Merkel Cell Carcinoma Dependence on Bcl-2 Family Members for Survival 
Merkel cell carcinoma (MCC), a rare but aggressive cutaneous neoplasm with high metastatic potential, has a poor prognosis at late stages of disease with no proven chemotherapeutic regimens. Using an enriched culture medium, we established and characterized 11 MCC cell lines for Bcl-2 family profiling and functional studies. Immunoblot analysis revealed collectively high protein levels of pro-survival Bcl-2 members in cell lines and a panel of MCC tumors. Down-regulation of individual Bcl-2 proteins by RNAi promoted death in a subset of MCC cell lines, whereas simultaneous inhibition of multiple family members using the small molecule antagonist ABT-263 led to dramatic induction of cell death in 10 of 11 lines. ABT-263 induced Bax-dependent apoptosis with rapid cleavage of caspase-3 and PARP, regardless of Bcl-2 family profile or presence of Merkel cell polyomavirus. Furthermore, ABT-263 treatment led to rapid and sustained growth suppression of MCC xenografts from a representative cell line, accompanied by a striking increase in apoptosis. Our results establish that concurrent inhibition of multiple pro-survival Bcl-2 proteins leads to effective induction of apoptosis, and strongly support the concept that targeting MCC addiction to these molecules may be useful therapeutically by reversing an intrinsic resistance to cell death.
doi:10.1038/jid.2014.138
PMCID: PMC4181590  PMID: 24614157
17.  IL-9 Regulates Allergen-Specific Th1 Responses in Allergic Contact Dermatitis 
The cytokine IL-9, derived primarily from T-helper (Th)-9 lymphocytes, promotes expansion of the Th2 subset and is implicated in the mechanisms of allergic asthma. We hypothesize that IL-9 also plays a role in human allergic contact dermatitis (ACD). To investigate this hypothesis, skin biopsy specimens of positive patch test sites from non-atopic patients were assayed using qPCR and immunohistochemistry. Along with Th2 associated cytokines, IFN-γ, IL-4, and IL-17A, expression of IL-9, and PU.1, a Th9-associated transcription factor, were elevated when compared to paired normal skin. Immunohistochemistry on ACD skin biopsies identified PU.1+CD3+, and PU.1+CD4+ cells, consistent with Th9 lymphocytes, in the inflammatory infiltrate. PBMC from nickel-allergic patients, but not non-allergic controls, show significant IL-9 production in response to nickel. Blocking studies with monoclonal antibodies to HLA-DR (but not HLA-A, B, C) or chloroquine significantly reduced this nickel-specific IL-9 production. Additionally, blockade of IL-9 or IL-4 enhanced allergen-specific IFN-γ production. A contact hypersensitivity model using IL-9−/− mice, shows enhanced Th1 lymphocyte immune responses, when compared to WT mice, consistent with our human in vitro data. This study demonstrates that IL-9, through its direct effects on Th1 and ability to promote IL-4 secretion, has a regulatory role for Th1 lymphocytes in ACD.
doi:10.1038/jid.2014.61
PMCID: PMC4303591  PMID: 24487305
18.  Tumor Necrosis Factor-Alpha and Apoptosis Induction in Melanoma Cells through Histone Modification by 3-Deazaneplanocin A 
doi:10.1038/jid.2013.489
PMCID: PMC4300195  PMID: 24226421
TNFα; DZNep; histone; melanoma; methylation
19.  [No title available] 
PMCID: PMC4296323  PMID: 24284421
20.  [No title available] 
PMCID: PMC4291112  PMID: 24522433
21.  Impaired proteasome function activates GATA3 in T-cells and upregulates CTLA-4: relevance for Sezary syndrome 
Highly regulated expression of the negative co-stimulatory molecule CTLA-4 on T-cells modulates T-cell activation and proliferation. CTLA-4 is preferentially expressed in Th2 T-cells, whose differentiation depends on the transcriptional regulator GATA3. Sezary syndrome (SS) is a T-cell malignancy characterized by Th2 cytokine skewing, impaired T-cell responses, and over-expression of GATA3 and CTLA-4. GATA3 is regulated by phosphorylation and ubiquitination. In SS cells, we detected increased polyubiquitinated proteins and activated GATA3. We hypothesized that proteasome dysfunction in SS T cells may lead to GATA3, and CTLA-4 over-expression. To test this hypothesis, we blocked proteasome function with bortezomib in normal T-cells, and observed sustained GATA3 and CTLA-4 upregulation. The increased CTLA-4 was functionally inhibitory in a mixed lymphocyte reaction (MLR). GATA3 directly transactivated the CTLA-4 promoter, and knockdown of GATA3 mRNA and protein inhibited CTLA-4 induction mediated by bortezomib. Finally, knockdown of GATA3 in patient’s malignant T-cells suppressed CTLA-4 expression. Here we demonstrate a new T-cell regulatory pathway that directly links decreased proteasome degradation of GATA-3, CTLA-4 upregulation, and inhibition of T-cell responses. We also demonstrate the presence of the GATA3/CTLA-4 regulatory pathway in fresh neoplastic CD4+ T-cells. Targeting of this pathway may be beneficial in SS and other CTLA-4-overexpressing T-cell neoplasms.
doi:10.1038/jid.2012.265
PMCID: PMC4284066  PMID: 22951729
22.  Transcriptome analysis of psoriasis in a large case-control sample: RNA-seq provides insights into disease mechanisms 
To increase our understanding of psoriasis, we utilized RNA-seq to assay the transcriptomes of lesional psoriatic and normal skin. We sequenced polyadenylated RNA-derived cDNAs from 92 psoriatic and 82 normal punch biopsies, generating an average of ~38 million single-end 80-bp reads per sample. Comparison of 42 samples examined by both RNA-seq and microarray revealed marked differences in sensitivity, with transcripts identified only by RNA-seq having much lower expression than those also identified by microarray. RNA-seq identified many more differentially expressed transcripts enriched in immune system processes. Weighted gene co-expression network analysis (WGCNA) revealed multiple modules of coordinately expressed epidermal differentiation genes, overlapping significantly with genes regulated by the long non-coding RNA TINCR, its target gene, staufen-1 (STAU1), the p63 target gene ZNF750, and its target KLF4. Other coordinately expressed modules were enriched for lymphoid and/or myeloid signature transcripts and genes induced by IL-17 in keratinocytes. Dermally-expressed genes were significantly down-regulated in psoriatic biopsies, most likely due to expansion of the epidermal compartment. These results demonstrate the power of WGCNA to elucidate gene regulatory circuits in psoriasis, and emphasize the influence of tissue architecture in both differential expression and co-expression analysis.
doi:10.1038/jid.2014.28
PMCID: PMC4057954  PMID: 24441097
skin; inflammation; immunology; cytokine; dermatology; psoriasis; transcriptome; network analysis
23.  Loss of Mpzl3 Function Causes Various Skin Abnormalities and Greatly Reduced Adipose Depots 
The rough coat (rc) spontaneous mutation causes sebaceous gland hypertrophy, hair loss and extracutaneous abnormalities including growth retardation. The rc mice have a missense mutation in the predicted immunoglobulin protein Mpzl3. In this study, we generated Mpzl3 knockout mice to determine its functions in the skin. Homozygous Mpzl3 knockout mice showed unkempt and greasy hair coat and hair loss soon after birth. Histological analysis revealed severe sebaceous gland hypertrophy and increased dermal thickness, but did not detect significant changes in the hair cycle. Mpzl3 null mice frequently developed inflammatory skin lesions; however, the early onset skin abnormalities were not the results of immune defects. The abnormalities in the Mpzl3 knockout mice resemble closely those observed in the rc/rc mice, as well as mice heterozygous for both the rc and Mpzl3 knockout alleles, indicating that rc and Mpzl3 are allelic. Using a lacZ reporter gene, we detected Mpzl3 promoter activity in the companion layer and inner root sheath of the hair follicle, sebaceous gland, and epidermis. Loss of MPZL3 function also caused a striking reduction in cutaneous and overall adipose tissue. These data reveal a complex role for Mpzl3 in the control of skin development, hair growth and adipose cell functions.
doi:10.1038/jid.2014.94
PMCID: PMC4057944  PMID: 24531688
Mpzl3; sebaceous gland; hair follicle; alopecia; adipose
24.  Changes in dermal fibroblasts from Abcc6−/− mice are present before and after the onset of ectopic tissue mineralization 
Pseudoxanthoma elasticum (PXE), a rare genetic disease caused by mutations in the ABCC6 gene, is characterized by progressive calcification of elastic fibers in the skin, eyes and the cardiovascular system. The pathomechanisms of the mineralization is still obscure. Several hypotheses have been proposed, one of them suggesting a role for fibroblasts in controlling the amount and the quality of the calcified extracellular matrix. This hypothesis raises the question whether changes in mesenchymal cells are the cause and/or the consequences of the calcification process. In this study, fibroblasts were isolated and cultured from Abcc6+/+ and Abcc6−/− mice of different ages in order to investigate parameters known to be associated with the phenotype of fibroblasts from PXE patients. Results demonstrate few changes (Ank and Opn down-regulation) are already present before the occurrence of calcification. By contrast, a modification of other parameters (intracellular O2− content, Tnap activity and Bmp2 up-regulation) can be observed in Abcc6−/− mice after the onset of tissue mineralization. These data suggest that in the Abcc6−/− genotype, dermal fibroblasts actively contribute to changes that promote matrix calcification and that these cells can be further modulated with time by the calcified environment, thus contributing to the age-dependent progression of the disease.
doi:10.1038/jid.2014.88
PMCID: PMC4057957  PMID: 24670382

Results 1-25 (815)