Inhibitory effects and target genes of bone morphogenetic protein 6 in Jurkat TAg cells

Abstract

Bone morphogenetic proteins (BMP) are multifunctional cytokines that belong to the TGF-b superfamily. BMP have been shown to regulate haematopoietic stem cells, B lymphopoiesis and early thymocyte differentiation. In the present study we explored the role of BMP-6 in Jurkat TAg cells. BMP-6 rapidly induced phosphorylation of Smad1/5/8, p38 and ERK1/2, followed by a potent up-regulation of ID1, ID2 and ID3. ID1 and ID3 were also induced at the protein level. Genome-wide expression profiling of cells treated with BMP-6 compared to medium confirmed that ID1-ID3 were target genes of BMP-6 together with Noggin and Smad6. Furthermore, several genes involved in transcriptional regulation were also identified, including NFKBIA, HEY1, DLX2, KLF10 and early growth response 1. Stimulation with BMP-6 exerted an antiproliferative effect that was counteracted by inhibitor of DNA binding (Id)1 siRNA, indicating that Id1 is an important downstream mediator in Jurkat TAg cells. A subset of CD4 + T cells were found to express the BMP receptors Alk-2 and Alk-3 (type I), in addition to BMPRII (type II). BMP-6 also induced phosphorylation of Smad1/5/8, followed by transcriptional increase in ID1-ID3 mRNA expression. However, we did not observe significant changes in Id protein expression in CD4 + T cells. Altogether, the data indicate a role for BMP-6 in human T lineage cells.

MicroRNA miR-155 Inhibits Bone Morphogenetic Protein (BMP) Signaling and BMP-Mediated Epstein-Barr Virus Reactivation

“…While activation of BMP signaling appears to contribute to some cancer types, it inhibits other cancer types by promoting growth arrest and differentiation and by inducing senescence (1). In immune cells, BMP signaling has been shown by multiple groups to inhibit lymphocyte activation, maturation, and growth (2,6,13,18,19,37). Here, we show that miR-155 inhibits BMP signaling by targeting multiple factors in the BMP signal transduction cascade.…”

“…In addition to EBV-associated malignancies, high levels of miR-155 are also observed in other lymphoid malignancies such as diffuse large B-dell lymphomas (DLBCL) (9,21). A number of studies have now provided evidence that BMP signaling can inhibit B-and T-cell growth at various stages of lymphoid development (2,6,13,18,19,37). Although it is likely that miR-155 contributes to oncogenesis at multiple levels, an ability to suppress BMP-mediated growth arrest signaling could be at least one contributing factor in tumor development/survival for some of these tumors.…”

Differential effects of inhibition of bone morphogenic protein (BMP) signalling on T‐cell activation and differentiation

“…In fact, previous reports have suggested that BMPs regulate T-cell proliferation. BMP4 and BMP6 have been reported to increase proliferation, while BMP2 decreased proliferation [17,18]. Considering the diversity of BMP ligands and receptors, DM may have a profound effect on T-cell proliferation by inhibiting BMP signal transduction via a wide range of BMP ligands and receptors.…”

BMP-6 in Renal Cell Carcinoma Promotes Tumor Proliferation through IL-10–Dependent M2 Polarization of Tumor-Associated Macrophages

“…Although originally reported as factors that induce bone and cartilage formation (3), BMPs have been shown to be critical for development (4)(5)(6). More recently, we and others have reported that BMPs regulate the immune system as BMP-6 inhibits B-and T-cell proliferation (7,8) and activates macrophages (9,10). In the context of RCC, BMP-4, -6, and -7 are often overexpressed (11,12), whereas BMP antagonist Sclerostin domain-containing-1 (SOSTDC1) is downregulated (13).…”