RESUMO
Fatty acid-binding proteins (FABPs) are postulated to serve as lipid shuttles that solubilize hydrophobic fatty acids and deliver them to appropriate intracellular sites. Epidermal FABP (E-FABP/FABP5) is predominantly expressed in keratinocytes and is overexpressed in the actively proliferating tissue characteristic of psoriasis and wound healing. In this study, we found decreased expression of the differentiation-specific proteins keratin 1, involucrin, and loricrin in E-FABP(-/-) keratinocytes relative to E-FABP(+/+) keratinocytes. We also determined that incorporation of linoleic acid was significantly reduced in E-FABP(-/-) keratinocytes. Although linoleic acid did not directly affect keratinocyte differentiation, keratin 1 expression was induced by the linoleic acid derivative 13(S)-hydroxyoctadecadienoic acid (13(S)-HODE), and this induction was concomitant with increased NF-κB activity. In E-FABP(-/-) keratinocytes, the expression of 13(S)-HODE and the subsequent induction of NF-κB activity was lower than in wild-type keratinocytes. The reduction of linoleic acid in E-FABP(-/-) keratinocytes led to decreased cellular 13(S)-HODE content, resulting in decreased keratin 1 expression through downregulation of NF-κB activity. The regulation of fatty acid metabolism by E-FABP during keratinocyte differentiation suggests that E-FABP may have a role in the pathogenesis of psoriasis.
Assuntos
Diferenciação Celular/fisiologia , Proteínas de Ligação a Ácido Graxo/metabolismo , Queratinócitos/citologia , Queratinócitos/metabolismo , Ácidos Linoleicos/metabolismo , NF-kappa B/metabolismo , Proteínas de Neoplasias/metabolismo , Transdução de Sinais/fisiologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Epiderme/metabolismo , Proteínas de Ligação a Ácido Graxo/deficiência , Proteínas de Ligação a Ácido Graxo/genética , Ácidos Graxos/metabolismo , Queratina-1/metabolismo , Ácido Linoleico/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Proteínas de Neoplasias/deficiência , Proteínas de Neoplasias/genética , Precursores de Proteínas/metabolismo , Psoríase/metabolismo , Psoríase/fisiopatologiaAssuntos
Adenocarcinoma/patologia , Neoplasias dos Genitais Masculinos/patologia , Genitália Masculina/patologia , Doença de Paget Extramamária/patologia , Transativadores/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Adenocarcinoma/metabolismo , Humanos , Masculino , Metaplasia/patologia , Pessoa de Meia-Idade , Invasividade Neoplásica/patologia , Neoplasias de Células Escamosas/patologia , Fatores de Transcrição , Proteína Supressora de Tumor p53/metabolismoRESUMO
p63/p51, a homolog of the tumor suppressor protein p53, is chiefly expressed in epithelial tissues, including the epidermis. p63 affects cell death similar to p53, and also plays important roles in the development of epithelial tissues and the maintenance of epithelial stem cells. Because it remains unclear how p63 regulates epithelial cell differentiation, we examined the function(s) of p63 in keratinocyte differentiation through the use of a keratinocyte culture system. DeltaNp63alpha (DeltaNp51B), a p63 isoform specifically expressed in basal keratinocytes, suppressed the differentiation of specific late-stage proteins, such as filaggrin and loricrin. In contrast, DeltaNp63alpha induced keratin 1 (K1), which is expressed at the start of differentiation, via c-Jun N-terminal kinase (JNK)/AP-1 activation. However, p63 did not induce K1 expression in the basal layer in vivo, although basal keratinocytes had high levels of p63. This discrepancy was explained by the suppression of K1 expression by dermis-secreted keratinocyte growth factor. This suppression occurred via extracellular signal-related kinase (ERK) signaling, and counteracted the p63-mediated induction of K1. Thus, a precise balance between p63 and keratinocyte growth factor mediates the onset of epithelial cell differentiation, through JNK and ERK signaling. These data may provide mechanistic explanations for the pathological features of skin diseases, including psoriasis.