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1.
Mol Cell ; 72(3): 444-456.e7, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30401431

RESUMO

Skin sun exposure induces two protection programs: stress responses and pigmentation, the former within minutes and the latter only hours afterward. Although serving the same physiological purpose, it is not known whether and how these programs are coordinated. Here, we report that UVB exposure every other day induces significantly more skin pigmentation than the higher frequency of daily exposure, without an associated increase in stress responses. Using mathematical modeling and empirical studies, we show that the melanocyte master regulator, MITF, serves to synchronize stress responses and pigmentation and, furthermore, functions as a UV-protection timer via damped oscillatory dynamics, thereby conferring a trade-off between the two programs. MITF oscillations are controlled by multiple negative regulatory loops, one at the transcriptional level involving HIF1α and another post-transcriptional loop involving microRNA-148a. These findings support trait linkage between the two skin protection programs, which, we speculate, arose during furless skin evolution to minimize skin damage.


Assuntos
Fator de Transcrição Associado à Microftalmia/metabolismo , Pele/metabolismo , Pele/efeitos da radiação , Animais , Linhagem Celular , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Masculino , Melanócitos/fisiologia , Melanócitos/efeitos da radiação , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/fisiologia , Fator de Transcrição Associado à Microftalmia/efeitos da radiação , Cultura Primária de Células , Pigmentação da Pele/efeitos da radiação , Raios Ultravioleta/efeitos adversos
2.
Commun Biol ; 7(1): 574, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38750105

RESUMO

Metastases are the major cause of cancer-related death, yet, molecular weaknesses that could be exploited to prevent tumor cells spreading are poorly known. Here, we found that perturbing hydrolase transport to lysosomes by blocking either the expression of IGF2R, the main receptor responsible for their trafficking, or GNPT, a transferase involved in the addition of the specific tag recognized by IGF2R, reduces melanoma invasiveness potential. Mechanistically, we demonstrate that the perturbation of this traffic, leads to a compensatory lysosome neo-biogenesis devoided of degradative enzymes. This regulatory loop relies on the stimulation of TFEB transcription factor expression. Interestingly, the inhibition of this transcription factor playing a key role of lysosome production, restores melanomas' invasive potential in the absence of hydrolase transport. These data implicate that targeting hydrolase transport in melanoma could serve to develop new therapies aiming to prevent metastasis by triggering a physiological response stimulating TFEB expression in melanoma.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Hidrolases , Lisossomos , Melanoma , Humanos , Melanoma/genética , Melanoma/patologia , Melanoma/metabolismo , Lisossomos/metabolismo , Hidrolases/metabolismo , Hidrolases/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Linhagem Celular Tumoral , Receptor IGF Tipo 2/metabolismo , Receptor IGF Tipo 2/genética , Metástase Neoplásica , Transporte Proteico , Regulação Neoplásica da Expressão Gênica
3.
J Invest Dermatol ; 138(10): 2216-2223, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29679610

RESUMO

Melanoma, a melanocyte origin neoplasm, is the most lethal type of skin cancer, and incidence is increasing. Several familial and somatic mutations have been identified in the gene encoding the melanocyte lineage master regulator, MITF; however, the neoplastic mechanisms of these mutant MITF variants are mostly unknown. Here, by performing unbiased analysis of the transcriptomes in cells expressing mutant MITF, we identified calcium-binding protein S100A4 as a downstream target of MITF-E87R. By using wild-type and mutant MITF melanoma lines, we found that both endogenous wild-type and MITF-E87R variants occupy the S100A4 promoter. Remarkably, whereas wild-type MITF represses S100A4 expression, MITF-E87R activates its transcription. The opposite effects of wild-type and mutant MITF result in opposing cellular phenotypes, because MITF-E87R via S100A4 enhanced invasion and reduced adhesion in contrast to wild-type MITF activity. Finally, we found that melanoma patients with altered S100A4 expression have poor prognosis. These data show that a change in MITF transcriptional activity from repression to activation of S100A4 that results from a point mutation in MITF alters melanoma invasive ability. These data suggest new opportunities for diagnosis and treatment of metastatic melanoma.


Assuntos
DNA de Neoplasias/genética , Regulação Neoplásica da Expressão Gênica , Melanoma/genética , Fator de Transcrição Associado à Microftalmia/genética , Mutação , Proteína A4 de Ligação a Cálcio da Família S100/genética , Neoplasias Cutâneas/genética , Análise Mutacional de DNA , Progressão da Doença , Humanos , Immunoblotting , Melanoma/metabolismo , Melanoma/patologia , Fator de Transcrição Associado à Microftalmia/metabolismo , Proteína A4 de Ligação a Cálcio da Família S100/biossíntese , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Células Tumorais Cultivadas
4.
Sci Rep ; 3: 2893, 2013 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-24113121

RESUMO

In this study, we conduct an in-depth analysis of annexin proteins from a diverse range of invertebrate taxa, including the major groups that contain the parasites and vector organisms that are harmful to humans and domestic animals. Using structure-based amino acid sequence alignments and phylogenetic analyses, we present a classification for this protein group and assign names to sequences with ambiguous annotations in public databases. Our analyses reveal six distinct annexin clades, and the mapping of genes encoding annexins to the genome of the human blood fluke Schistosoma mansoni supports the hypothesis of gene duplication as a major evolutionary event in annexin genesis. This study illuminates annexin diversity from a novel perspective using contemporary phylogenetic hypotheses of eukaryote evolution, and will aid the consolidation of annexin protein identities in public databases and provide a foundation for future functional analysis and characterisation of these proteins in parasites of socioeconomic importance.


Assuntos
Anexinas/genética , Estudo de Associação Genômica Ampla , Animais , Anexinas/química , Mapeamento Cromossômico , Bases de Dados Genéticas , Evolução Molecular , Humanos , Invertebrados/classificação , Invertebrados/genética , Filogenia
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