RESUMEN
Metastasis-associated protein 3 (MTA3) is a recently described cell-type specific component of the Mi-2-NURD transcriptional co-repressor complex that is expressed in breast epithelia and germinal centre B cells. In model B cell lines, MTA3 physically interacts with BCL6 and appears to be instrumental in maintenance of the germinal centre B cell transcriptional programme that precludes premature plasmacytic differentiation. Here, we report selective, in situ cell-type specific expression of MTA3 among lymphoid cells largely confined to the germinal centre B cell compartment. Centroblasts display greater expression than smaller, less proliferative centrocytes, with undetectable expression in quiescent plasma cells. Among B cell neoplasms, germinal centre B cell-like lymphomas likewise exhibit selective expression that generally escalates with increasing proliferative capacity. MTA3 protein expression was, in accord, highly predictive of the germinal centre B cell-like gene expression profile for diffuse large B cell lymphomas. Lastly, relative repression of a subset of known BCL6 targets, including BLIMP1 and p27kip1, was highest in diffuse large B cell lymphomas that co-expressed both MTA3 and BCL6 protein. Together, these novel data suggest a role for MTA3 in BCL6-mediated lymphomagenesis in germinal centre B cell-like neoplasms.
Asunto(s)
Linfocitos B/metabolismo , Regulación Neoplásica de la Expresión Génica , Centro Germinal/metabolismo , Linfoma de Células B/metabolismo , Proteínas de Neoplasias/análisis , Inhibidor p27 de las Quinasas Dependientes de la Ciclina , Expresión Génica , Perfilación de la Expresión Génica , Marcadores Genéticos , Humanos , Inmunohistoquímica , Péptidos y Proteínas de Señalización Intracelular/genética , Linfoma de Células B/genética , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/metabolismo , Proteínas de Neoplasias/genética , Análisis de Secuencia por Matrices de Oligonucleótidos , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Proteínas Proto-Oncogénicas c-bcl-6/análisis , Proteínas Proto-Oncogénicas c-bcl-6/genética , Proteínas Represoras/genética , Factores de Transcripción/genéticaRESUMEN
Ingesting phenolic phytochemicals in many plant products may promote health, but the effects of phenolic phytochemicals at the cellular level have not been fully examined. Thus, it was determined if the tea phenolic phytochemical, epigallocatechin gallate (EGCG), protects U937 human pro-monocytic cells against the nitrogen free radical, nitric oxide (*NO). Cells were incubated for 4-6 h with 500 microM S-nitrosoglutathione (GSNO), which generates *NO, but this did not induce single-strand breaks in DNA. Nevertheless, 82 +/- 4% of GSNO-treated cells, compared to only 39 +/- 1% of untreated cells, were arrested in the G(1)-phase of the cell cycle. However, dosing the GSNO-treated cells with 9, 14, or 18 microg/ml of EGCG resulted in only 74 +/- 8%, 66 +/- 1%, and 43 +/- 3% of the cells, respectively, in the G(1)-phase. Exposing cells to GSNO also resulted in the emergence of a sub-G(1) apoptotic cell population numbering 14 +/- 3%, but only 5 +/- 2%, 5 +/- 1%, and 2 +/- 0% upon dosing of the GSNO-treated cells with 9, 14, and 18 microg/ml of EGCG, respectively. Furthermore, exposing cells to GSNO resulted in greater cell surface binding of annexin V-FITC, but binding was 41-89% lower in GSNO-treated cells dosed with EGCG. Collectively, these data suggest that *NO or downstream products induced cell cycle arrest and apoptosis that was not due to single-strand breaks in DNA, and that EGCG scavenged cytotoxic *NO or downstream products, thus reducing the number of cells in a state of cell cycle arrest or apoptosis.
