PMC:1134658 / 1403-4028
Annnotations
{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/1134658","sourcedb":"PMC","sourceid":"1134658","source_url":"http://www.ncbi.nlm.nih.gov/pmc/1134658","text":"Background\nMembers of the transforming growth factor β (TGF-β) superfamily play central roles in controlling cellular proliferation, differentiation, migration and apoptosis [1]. These cytokines can be divided into three subgroups: TGF-β, the activins/inhibins, and the bone morphogenetic proteins (BMPs), of which the latter constitute the largest family. BMPs are 30–38 kDa hetero- or homodimeric proteins originally identified by their ability to induce ectopic cartilage and bone formation [2,3]. Several studies have demonstrated an essential role of these proteins during embryogenesis, and more recently, also in adult tissues [1]. TGF-β has been intensively studied in normal and malignant haematopoietic cells and is one of the most potent endogenous negative regulators known to date. [4]. In contrast, the effect of BMPs in the immune system has not been widely investigated. In that respect, BMP- 2, -4 and -7 have been found to control differentiation of hematopoietic stem cells [5] and early T cell development [6,7]. BMP-6 has been reported to reduce the number of cobblestone-area-forming cells of normal human haematopoietic cells [8]. Furthermore, BMP-2, -4, 6 and -7 had an antiproliferative and a proapoptotic effect on multiple myeloma cells [9-11]. In addition, by gene expression profiling, BMP-6 significantly increased the predictive value for a multi-gene signature test and was associated with a poor outcome in diffuse large B cell lymphomas (DLBCL) [12].\nBMP-6, like the other BMP members, signals through ligation and heterodimerzation of BMP type I [activin-like-kinase (ALK)] and type II serine-threonine kinase receptors, which subsequently propagates the signal downstream by phosphorylating Smad proteins. BMP-6 can signal through the ligation of the type I receptors Act-RIA, BMP-RIA, and BMP-RIB and the type II receptors BMP-RII, Act-RIIA and Act-RIIB, which lead to the phosphorylation of the receptor Smads (Smad-1, Smad-5, and Smad-8). The R- Smads then form complexes with the co-Smad (Smad4) and are translocated into the nucleus where they exert gene regulation [1,13].\nGiven the reported role of BMP-6 in B-cell malignancies and haematopoietic progenitor cells, we wanted to explore its potential role in normal human B cells. We studied the effects of BMP-6 on proliferation and apoptosis on resting and stimulated B cells. Furthermore, the expression of BMP receptors and BMP-6 induced activation of the Smad signalling pathway with subsequent regulation of the target genes Id1–Id4, were resolved. Finally, we investigated whether B cells also were capable of producing 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