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1.
Proc Natl Acad Sci U S A ; 105(12): 4838-43, 2008 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-18359851

RESUMEN

The hedgehog (Hh) signaling pathway regulates the development of many organs in mammals, and activation of this pathway is widely observed in human cancers. Although it is known that Hh signaling activates the expression of genes involved in cell growth, the precise role of the Hh pathway in cancer development is still unclear. Here, we show that constitutively activated mutants of Smoothened (Smo), a transducer of the Hh signaling pathway, inhibit the accumulation of the tumor suppressor protein p53. This inhibition was also observed in the presence of Hh ligand or with the overexpression of the transcription factors Gli1 and Gli2, downstream effectors of Smo, indicating that this inhibition is specific for the Hh pathway. We also report that Smo mutants augment p53 binding to the E3 ubiquitin-protein ligase Mdm2 and promote p53 ubiquitination. Furthermore, Hh signaling induced the phosphorylation of human Mdm2 protein on serines 166 and 186, which are activating phosphorylation sites of Mdm2. Smo mutants enhanced the proliferation of mouse embryonic fibroblasts (MEFs) while inducing a DNA-damage response. Moreover, Smo partially inhibited p53-dependent apoptosis and cell growth inhibition in oncogene-expressing MEFs. We also found that accumulation of p53 is inhibited by Hh signaling in several human cancer cell lines. Therefore, the Hh pathway may be a powerful accelerator of oncogenesis by activating cell proliferation and inhibiting the p53-mediated anti-cancer barrier induced by oncogenic stress.


Asunto(s)
Proteínas Hedgehog/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transducción de Señal , Proteína p53 Supresora de Tumor/metabolismo , Animales , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Daño del ADN , Regulación hacia Abajo/genética , Ratones , Fosforilación/efectos de los fármacos , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Receptor Smoothened , Proteína p53 Supresora de Tumor/genética , Ubiquitinación/efectos de los fármacos , Alcaloides de Veratrum/farmacología
2.
Cancer Invest ; 26(7): 680-8, 2008 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-18608210

RESUMEN

The expression of p53-target genes encoding the proapoptotic factor Noxa, but not PUMA, was not induced by p53 in HCT116 and SW480 cells, which show resistance to apoptosis in response to p53 overexpression. The lack of p53 inducibility of Noxa was restored by treatment with the DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine (5-aza-CdR). Furthermore, p53 induced apoptosis in HCT116 and SW480 cells treated with 5-aza-CdR. Moreover, the inhibition of Noxa expression by RNAi in 5-aza-CdR-treated HCT116 cells resulted in the partial inhibition of p53-induced apoptosis. These results suggest that epigenetic cancer therapy is possible for some cancers in combination with forced p53 activation.


Asunto(s)
Antimetabolitos Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Azacitidina/análogos & derivados , Neoplasias/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismo , Azacitidina/farmacología , Ciclo Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Metilasas de Modificación del ADN/antagonistas & inhibidores , Metilasas de Modificación del ADN/metabolismo , Decitabina , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HCT116 , Humanos , Neoplasias/enzimología , Neoplasias/genética , Neoplasias/patología , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Interferencia de ARN , Factores de Tiempo , Proteína p53 Supresora de Tumor/genética
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