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Important Negative Regulator (important + negative_regulator)
Selected AbstractsThe Wnt antagonist secreted frizzled-related protein-1 controls osteoblast and osteocyte apoptosisJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2005Peter V.N. Bodine Abstract Mechanisms controlling human bone formation remain to be fully elucidated. We have used differential display-polymerase chain reaction analysis to characterize osteogenic pathways in conditionally immortalized human osteoblasts (HOBs) representing distinct stages of differentiation. We identified 82 differentially expressed messages and found that the Wnt antagonist secreted frizzled-related protein (sFRP)-1 was the most highly regulated of these. Transient transfection of HOBs with sFRP-1 suppressed canonical Wnt signaling by 70% confirming its antagonistic function in these cells. Basal sFRP-1 mRNA levels increased 24-fold during HOB differentiation from pre-osteoblasts to pre-osteocytes, and then declined in mature osteocytes. This expression pattern correlated with levels of cellular viability such that the pre-osteocytes, which had the highest levels of sFRP-1 mRNA, also had the highest rate of cell death. Basal sFRP-1 mRNA levels also increased 29-fold when primary human mesenchymal stem cells were differentiated to osteoblasts supporting the developmental regulation of the gene. Expression of sFRP-1 mRNA was induced 38-fold following prostaglandin E2 (PGE2) treatment of pre-osteoblasts and mature osteoblasts that had low basal message levels. In contrast, sFRP-1 expression was down-regulated by as much as 80% following transforming growth factor (TGF)-,1 treatment of pre-osteocytes that had high basal mRNA levels. Consistent with this, treatment of pre-osteoblasts and mature osteoblasts with PGE2 increased apoptosis threefold, while treatment of pre-osteocytes with TGF-,1 decreased cell death by 50%. Likewise, over-expression of sFRP-1 in HOBs accelerated the rate of cell death threefold. These results establish sFRP-1 as an important negative regulator of human osteoblast and osteocyte survival. © 2005 Wiley-Liss, Inc. [source] SHP-1 expression in primary central nervous system B-cell lymphomas in immunocompetent patients reflects maturation stage of normal B cell counterpartsPATHOLOGY INTERNATIONAL, Issue 9 2004Yasuo Sugita SHP-1 is an important negative regulator involved in signaling through receptors for cytokine/growth factors, and differential patterns of SHP-1 expression in several types of B-cell lymphomas closely resemble the patterns seen in their normal B cell counterparts. In an effort to elucidate the origin of primary central nervous system lymphomas (PCNSL), the present study assessed 32 cases of PCNSL. Tumors were subclassified according to WHO classification and were evaluated by immunohistochemistry for expression of antigens associated with germinal center (GC) (CD10, Bcl-6) and non-GC stages (SHP-1, CD138). Twenty-nine cases showed diffuse large-cell centroblastic morphology, whereas three cases showed diffuse large-cell immunoblastic morphology. The immunophenotypes of PCNSL were as follows: SHP-1+/Bcl-6,/CD10,/CD138, (12 of 32 cases); SHP-1+/Bcl-6+/CD10,/CD138, (15 of 32 cases); SHP-1+/Bcl-6+/CD10+/CD138, (two of 32 cases); SHP-1+/Bcl-6,/CD10+/CD138, (one of 32 cases); and SHP-1,/Bcl-6,/CD10,/CD138, (two of 32 cases). These results indicate that PCNSL might be distinct lymphomas that originate from a late germinal center to an early postgerminal center. [source] PD-1/B7-H1 Interaction Contribute to the Spontaneous Acceptance of Mouse Liver AllograftAMERICAN JOURNAL OF TRANSPLANTATION, Issue 1 2010M. Morita The programmed death-1 (PD-1)/B7-H1 pathway acts as an important negative regulator of immune responses. We herein investigated the role of the PD-1/B7-H1 pathway in establishing an immunological spontaneous tolerance status in mouse liver allografting. B7-H1 is highly expressed on the donor-derived tissue cells and it is also associated with the apoptosis of infiltrating T cells in the allografts. Strikingly, a blockade of the PD-1/B7-H1 pathway via anti-B7-H1mAb or using B7-H1 knockout mice as a donor led to severe cell infiltration as well as hemorrhaging and necrosis, thus resulting in mortality within 12 days. Furthermore, the expression of the FasL, perforin, granzyme B, iNOS and OPN mRNA in the liver allografts increased in the antibody-treated group in comparison to the controls. Taken together, these data revealed that the B7-H1 upregulation on the tissue cells of liver allografts thus plays an important role in the apoptosis of infiltrating cells, which might play a critical role of the induction of the spontaneous tolerance after hepatic transplantation in mice. [source] Mice lacking cyclin-dependent kinase inhibitor p19Ink4d show strain-specific effects on male reproductionMOLECULAR REPRODUCTION & DEVELOPMENT, Issue 8 2007Gregory M. Buchold Abstract p19Ink4d is a member of the INK4 family of cyclin-dependent kinase inhibitors, which are important negative regulators of the G1-phase cyclin-dependent kinases CDK4 and CDK6. On a mixed C57BL/6,×,129P2/OlaHsd background, mice deficient for p19Ink4d exhibited defects in male reproductive function including testicular atrophy, alteration in serum follicle stimulating hormone, qualitative increase in germ cell apoptosis, and delayed kinetics of meiotic prophase markers (Zindy et al., 2001. Mol Cell Biol 21:3244,3255; Zindy et al., 2000. Mol Cell Biol 20:372,378). In this study, a quantitative assessment of these aspects of reproductive capacity demonstrated relatively mild deficits in p19Ink4d,/, males compared to controls. These effects did not dramatically worsen in older males although some seminiferous tubule defects were observed. Following marker-assisted backcrossing into the C57BL/6 background, p19Ink4d,/, males did not display defects in testis weights, sperm numbers, serum FSH, germ cell apoptosis, or kinetics of selected meiotic prophase markers. These studies indicate that a reduction in Ink4 family function by the loss of p19Ink4d is sufficient to induce mild reproductive defects in male mice with a mixed genetic background, but not in the C57BL/6 genetic background. Mol. Reprod. Dev. 74: 1008,1020, 2007. © 2007 Wiley-Liss, Inc. [source] Arabidopsis mitogen-activated protein kinase MPK12 interacts with the MAPK phosphatase IBR5 and regulates auxin signalingTHE PLANT JOURNAL, Issue 6 2009Jin Suk Lee Summary Mitogen-activated protein kinase (MAPK) phosphatases are important negative regulators in the MAPK signaling pathways responsible for many essential processes in plants, including development, stress management and hormonal responses. A mutation in INDOLE-3-BUTYRIC ACID-RESPONSE5 (IBR5), which is predicted to encode a dual-specificity MAPK phosphatase, was previously reported to confer reduced sensitivity to auxin and ABA in Arabidopsis roots. To further characterize IBR5, and to understand how it might help integrate MAPK cascades with hormone signaling, we searched for IBR5-interacting MAPKs. Yeast two-hybrid assays, in vitro binding assays and in vivo protein co-immunoprecipitation studies demonstrated that MPK12 and IBR5 are physically coupled. The C-terminus of MPK12 appears to be essential for its interaction with IBR5, and in vitro dephosphorylation and immunocomplex kinase assays indicated that activated MPK12 is efficiently dephosphorylated and inactivated by IBR5. MPK12 and IBR5 mRNAs are both widely expressed across Arabidopsis tissues, and at the subcellular level each protein is predominantly localized in the nucleus. In transgenic plants with reduced expression of the MPK12 gene, root growth is hypersensitive to exogenous auxins, but shows normal ABA sensitivity. MPK12 suppression in an ibr5 background partially complements the ibr5 auxin-insensitivity phenotype. Our results demonstrate that IBR5 is a bona fide MAPK phosphatase, and suggest that MPK12 is both a physiological substrate of IBR5 and a novel negative regulator of auxin signaling in Arabidopsis. [source] | |||||||||||||