BCL11 genes play crucial roles in lymphopoiesis and have been associated with hematopoietic malignancies. Specifically, disruption of the BCL11B (B-cell chronic lymphocytic leukemia/lymphoma 11B) locus is linked to T-cell acute lymphoblastic leukemia, and the loss of heterozygosity in mice results in T-cell lymphoma. BCL11 proteins are related C 2 H 2 zinc-finger transcription factors that act as transcriptional repressors. Here, we demonstrate the association of the endogenous BCL11B with the nucleosome remodeling and histone deacetylase (NuRD) complex, one of the major transcriptional corepressor complexes in mammalian cells. BCL11B complexes from T lymphocytes possess trichostatin A-sensitive histone deacetylase activity, confirming the functionality of the complexes. Analysis of the BCL11B-NuRD association demonstrated that BCL11B directly interacted with the metastasis-associated proteins MTA1 and MTA2 through the amino-terminal region. We provide evidence for the functional requirement of MTA1 in transcriptional repression mediated by BCL11B through the following: (1) overexpression of MTA1 enhanced the transcriptional repression mediated by BCL11B, (2) knockdown of MTA1 expression by small interfering RNA inhibited BCL11B transcriptional repression activity and (3) MTA1 was specifically recruited to a BCL11B targeted promoter. Taken together, these data support the hypothesis that the NuRD complex mediates transcriptional repression function of BCL11B.
Increasing evidence shows a crucial role of the Ca 2؉ / calcineurin-mediated activation of the nuclear factor of activated T cells (NFAT) in the regulation of a variety of processes in nonimmune cells. Here we provide evidence that NFATc1 and NFATc2 are expressed in human colon carcinoma cell lines. These proteins are translocated from the cytoplasm to the nucleus upon treatment with a combination of phorbol 12-myristate 13-acetate plus the calcium ionophore A23187. Subsequent to translocation to the nucleus, NFATc1 and NFATc2 were able to bind to a NFAT response element in the DNA, regulating transcriptional activation of genes containing a NFAT-responsive element such as cyclooxygenase-2 (COX-2). COX-2 expression and prostaglandin E 2 (PGE 2 ) production were induced upon pharmacological stimuli leading to NFAT activation and blunted by inhibition of calcineurin phosphatase with cyclosporin A or tacrolimus (FK506). Expression of NFAT wild type protein or the active catalytic subunit of calcineurin transactivates COX-2 promoter activity, whereas a dominant negative mutant of NFAT inhibited COX-2 induction in colon carcinoma cell lines. Furthermore, mutation or deletion of NFAT binding sites in the human COX-2 promoter greatly diminished its induction by phorbol 12-myristate 13-acetate/calcium ionophore A23187. These findings demonstrate the presence and activation of NFAT in human colon carcinoma cells, with important implications in the regulation of genes involved in the transformed phenotype as COX-2. The nuclear factor of activated T cells (NFAT)1 family of transcription factors was originally involved in the transcriptional regulation of a large number of inducible genes encoding cytokines and cell-surface receptors that are essential for a productive immune response (for review, see Refs. 1 and 2). However, recent evidence has confirmed that NFAT is expressed in cell types other than immune cells, regulating processes as diverse as cardiac valve formation, fiber-type specification in skeletal muscle, osteoclast differentiation, neuronal development, and angiogenesis, among others (3-6).The NFAT family is composed of four classical calcium-responsive members named NFATc1, NFATc2, NFATc3, and NFATc4 (2) and the recently identified calcium insensitive NFAT5 (7). NFAT proteins are located in the cytoplasm of unstimulated cells in a highly phosphorylated form. After an increase in intracellular calcium levels, NFAT proteins are dephosphorylated by calcineurin (Cn), a serine-threonine phosphatase, and translocate to the nucleus. Once in the nucleus, they bind to specific sequences in the DNA, therefore activating transcription of NFAT-dependent genes (2, 8).One of the genes that has been reported to be regulated by NFAT in non-lymphoid tissues is cyclooxygenase-2 (COX-2) (9 -11). Two isoforms of cyclooxygenase enzyme have been described, COX-1 and COX-2. Both isoforms catalyze the ratelimiting step in the conversion of arachidonic acid to prostaglandin H 2 , the common precursor of prostaglandins, prostacyclins...
Cyclooxygenase-2 (Cox-2), the gastrin-release peptide (GRP) and its cognate receptor (GRP-R) are overexpressed in a significant percentage of colorectal carcinomas and are associated with cell growth, invasiveness and tumor progression. However, a molecular link between all of them in adenocarcinomas has not been established. Here, we show that bombesin (BBS), a GRP homolog, stimulates the expression of Cox-2 mRNA and protein in human colon adenocarcinoma Caco-2 cells, resulting in enhanced release of prostaglandin E 2 . These effects were markedly inhibited by the specific BBS antagonist RC-3940-II. BBS promotes the activation of the nuclear factor of activated T cells (NFAT) through a Ca 2 þ /calcineurin (Cn)-linked pathway. Upon BBS stimulation, the NFATc1 isoform translocates into the nucleus with a concomitant increase in NFATc1 binding to two specific recognition sites in the promoter region of the Cox-2 gene. Furthermore, inhibition of Cn activity by the immunosuppressive drug cyclosporin A impaired NFAT activation and diminished Cox-2 expression in BBSstimulated cells. Interestingly, BBS pretreatment strongly enhances the invasive capacity of carcinoma cells, effect which was inhibited by a Cox-2-specific inhibitor. These findings provide the first evidence for the involvement of the Ca 2 þ /Cn/NFAT pathway in BBS-mediated induction of genes involved in colon carcinoma invasiveness such as Cox-2. Oncogene (2007) 26, 958-969.
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