RESUMEN
First time p53 was found in the complex with viral large T-antigene in the cells transformed by small DNA virus SV40. The cloning of p53 cDNA was done in the beginning of eighties and soon after that the whole p53 gene was cloned. The p53 family is comprised of three genes: TP53,TP63 and TP73, each of which is expressed as a set of structurally and functionally different isoforms. All of them intensively interact with each other forming a united functional network of proteins. In this review we discuss evolution of the p53 family and significance of all its members in embryonic development, reproduction, regeneration, regulation of aging and life span, as well as in the body's defense against cancer. With special attention we review the role of less studied members of the p53 family: p63 and p73, in oncogenesis and tumor progression and show that different isoforms of these proteins might exert a contrary effect on these processes.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Familia de Multigenes , Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Transactivadores/metabolismo , Proteína p53 Supresora de Tumor/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Animales , Proteínas de Unión al ADN/genética , Evolución Molecular , Humanos , Ratones , Neoplasias/genética , Proteínas Nucleares/genética , Fosfoproteínas/genética , Transactivadores/genética , Factores de Transcripción , Proteína Tumoral p73 , Proteína p53 Supresora de Tumor/genética , Proteínas Supresoras de Tumor/genéticaRESUMEN
p73, a new p53 family member, is a transcription factor that is increasingly recognized in cancer research as an important player in tumorigenesis as well as in chemotherapeutic drug sensitivity. Despite the substantial structural and functional similarities to p53, accumulating evidence suggests that p53 and p73 may differently regulate their transcriptional targets. In this study, we have investigated the role of p73 in regulation of the gastrin gene promoter. Gastrin is a peptide hormone and an important factor in determining the progression of a number of human malignancies. Our results show that p73 can bind to the gastrin promoter. This leads to transcriptional upregulation of gastrin mRNA. We also found that the levels of gastrin and p73 transcripts correlate in primary gastric tumors. Taken together, our results demonstrate a novel mechanism for regulation of gastrin gene transcription and support a concept that p53 and p73 may have different biological roles in tumors.
Asunto(s)
Proteínas de Unión al ADN/fisiología , Gastrinas/biosíntesis , Gastrinas/genética , Proteínas Nucleares/fisiología , Regiones Promotoras Genéticas , Proteínas Supresoras de Tumor/fisiología , Animales , Línea Celular Tumoral , Proteínas de Unión al ADN/genética , Gastrinas/metabolismo , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Ratones , Proteínas Nucleares/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiología , ARN Mensajero/biosíntesis , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Proteína Tumoral p73 , Proteínas Supresoras de Tumor/genéticaRESUMEN
Stromal cells in the tumor microenvironment play a key role in the metastatic properties of a tumor. It is recognized that cancer-associated fibroblasts (CAFs) and endothelial cells secrete factors capable of influencing tumor cell migration into the blood or lymphatic vessels. We developed a microfluidic device that can be used to image the interactions between stromal cells and tumor cell spheroids in a three dimensional (3D) microenvironment while enabling external control of interstitial flow at an interface, which supports endothelial cells. The apparatus couples a 200-µm channel with a semicircular well to mimic the interface of a blood vessel with the stroma, and the design allows for visualization of the interactions of interstitial flow, endothelial cells, leukocytes, and fibroblasts with the tumor cells. We observed that normal tissue-associated fibroblasts (NAFs) contribute to the "single file" pattern of migration of tumor cells from the spheroid in the 3D microenvironment. In contrast, CAFs induce a rapid dispersion of tumor cells out of the spheroid with migration into the 3D matrix. Moreover, treatment of tumor spheroid cultures with the chemokine CXCL12 mimics the effect of the CAFs, resulting in similar patterns of dispersal of the tumor cells from the spheroid. Conversely, addition of CXCL12 to co-cultures of NAFs with tumor spheroids did not mimic the effects observed with CAF co-cultures, suggesting that NAFs produce factors that stabilize the tumor spheroids to reduce their migration in response to CXCL12.
RESUMEN
p73 is a member of the p53 protein family. Although the tumor suppressor function of p53 is clearly defined, the role of p73 in tumorigenesis is still a matter of debate. A complex pattern of expression of p73 isoforms makes it difficult to unambiguously interpret the experimental results. Previously, we along with others have found that the N-terminally truncated isoform of p73, ΔNp73, has potent anti-apoptotic and oncogenic properties in vitro and in vivo. In this study, we analyzed, for the first time, the regulation of ΔNp73 in a large number of gastric, gastroesophageal junction and esophageal tumors. We found that expression of ΔNp73 mRNA and protein is increased in these neoplasms. Furthermore, the upregulation of the ΔNp73 protein is significantly associated with poor patient survival. Oncogenic properties of ΔNp73 were further confirmed by finding that ΔNp73 facilitates anchorage-independent growth of gastric epithelial cells in soft agar. As little is currently known about the regulation of ΔNp73 transcription, we investigated the alternative p73 gene promoter that mediates the ΔNp73 expression. Analyzing the ΔNp73 promoter in silico as well as by using chromatin immunoprecipitation, site-directed mutagenesis and deletion analyses, we identified the evolutionary conserved region within the ΔNp73 promoter that contains binding sites for HIC1 (hypermethylated in cancer) protein. We found that HIC1 negatively regulates ΔNp73 transcription in mucosal epithelial cells. This leads to a decrease in ΔNp73 protein levels and may normally control the oncogenic potential of the ΔNp73 isoform.
Asunto(s)
Proteínas de Unión al ADN/genética , Neoplasias Esofágicas/genética , Regulación Neoplásica de la Expresión Génica/genética , Proteínas Nucleares/genética , Regiones Promotoras Genéticas/genética , Neoplasias Gástricas/genética , Proteínas Supresoras de Tumor/genética , Secuencia de Bases , Inmunoprecipitación de Cromatina , Secuencia Conservada , Expresión Génica , Humanos , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Análisis de Secuencia por Matrices de Oligonucleótidos , Isoformas de Proteínas/genética , ARN Mensajero/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteína Tumoral p73RESUMEN
The p73 protein is a transcription factor and member of the p53 protein family that expresses as a complex variety of isoforms. DeltaNp73alpha is an N-terminally truncated isoform of p73. We found that DeltaNp73 protein is upregulated in human gastric carcinoma suggesting that DeltaNp73 may play an oncogenic role in these tumors. Although it has been shown that DeltaNp73alpha inhibits apoptosis and counteracts the effect of chemotherapeutic drugs, the underlying mechanism by which this p73 isoform contributes to chemotherapeutic drug response remains to be explored. We found that DeltaNp73alpha upregulates MDR1 mRNA and p-glycoprotein (p-gp), which is involved in chemotherapeutic drug transport. This p-gp upregulation was accompanied by increased p-gp functional activity in gastric cancer cells. Our data suggest that upregulation of MDR1 by DeltaNp73alpha is mediated by interaction with p53 at the MDR1 promoter.