RESUMO
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, p63gamma and p63beta (both TA and DeltaN isoforms) and TAp73beta isoform induce Shh. Expression of Shh was found to be significantly reduced in mouse embryo fibroblasts obtained from p63-/- mice. The naturally occurring p63 mutant TAp63gamma(R279H) and the tumor suppressor protein p14(ARF) inhibited the TAp63gamma-mediated transactivation of Shh. The region -228 to -102 bp of Shh promoter was found to be responsive to TAp63gamma-induced transactivation and TAp63gamma binds to regions within the Shh promoter in vivo. The results presented in this study implicate p63 in the regulation of the Shh signaling pathway.
Assuntos
Proteínas Hedgehog/metabolismo , Proteínas de Membrana/metabolismo , Fosfoproteínas/metabolismo , Transativadores/metabolismo , Ativação Transcricional , Animais , Sítios de Ligação , Linhagem Celular Tumoral , Células Cultivadas , Proteínas de Ligação a DNA/fisiologia , Proteínas Hedgehog/genética , Humanos , Proteínas de Membrana/fisiologia , Camundongos , Camundongos Knockout , Proteínas Nucleares/fisiologia , Fosfoproteínas/genética , Fosfoproteínas/fisiologia , Regiões Promotoras Genéticas , Transdução de Sinais , Transativadores/genética , Transativadores/fisiologia , Proteína Tumoral p73 , Proteína Supressora de Tumor p14ARF/fisiologia , Proteínas Supressoras de Tumor/fisiologiaRESUMO
Peptide-mediated internalization and organelle targeting of quantum dots.
Assuntos
Peptídeos/química , Pontos Quânticos , Apoptose/fisiologia , Membrana Celular/química , Membrana Celular/fisiologia , Fibroblastos/metabolismo , Células HeLa , Humanos , Células Jurkat , Organelas/química , Organelas/fisiologia , Peptídeos/fisiologia , SemicondutoresRESUMO
Transforming growth factor beta (TGFbeta) is a secreted protein present in the circulation and is a critical regulator of the body's immune system. TGFbeta is believed to control several components of the immune system and inhibit autoimmune reactions. Systemic lupus erythematosus (SLE) and Sjogren's syndrome (SS) are prototypical human autoimmune diseases characterized by the circulating autoantibodies directed against nuclear antigens and immune complex deposition in various tissues leading to target organ inflammation and damage. Although the etiology of SLE is unknown, it has been observed that patients with SLE have lower levels of circulating TGFbeta than healthy individuals. In addition, mice lacking the TGFbeta1 gene develop a severe autoimmune disease that has features of both SS and SLE. Polymorphisms in the TGFbeta1 gene may alter the mRNA expression levels and influence the plasma protein concentration. Of the known TGFbeta 1 polymorphisms, only the C-509T polymorphism in the promoter region has been shown to be significantly associated with the plasma concentrations of TGFbeta 1. In this study, we have conducted a blinded study to determine if the -509 TGFbeta1 gene polymorphism is associated with SS or SLE. Genomic PCR and RFLP analysis of a 441 bp sequence encompassing the -509 polymorphism of the TGFbeta gene indicated that there were no statistically significant clinical correlations.
