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Key Negative Regulator (key + negative_regulator)
Selected AbstractsMeiosis induced by inactivation of Pat1 kinase proceeds with aberrant nuclear positioning of centromeres in the fission yeast Schizosaccharomyces pombeGENES TO CELLS, Issue 8 2004Yuji Chikashige Nuclear organization of chromosomes proceeds with significant changes during meiosis. In the fission yeast Schizosaccharomyces pombe, centromeres are clustered at the spindle-pole body (SPB) during the mitotic cell cycle; however, during meiotic prophase telomeres become clustered to the SPB and centromeres dissociate from the SPB. We followed the movement of telomeres, centromeres and sister chromatids in living S. pombe cells that were induced to meiosis by inactivation of Pat1 kinase (a key negative regulator of meiosis). Time-course observation in living cells determined the temporal order of DNA synthesis, telomere clustering, centromere separation and meiotic chromosome segregation. When meiosis was induced by Pat1 inactivation at the G1 phase of mitosis, telomeres clustered to the SPB as per normal meiosis, but in most cells the centromeres remained partially associated with the SPB. When meiosis was initiated at the G2 phase by Pat1 inactivation, both telomeres and centromeres retained their mitotic nuclear positions in the majority of cells. These results indicate that the progression of meiosis induced by Pat1 inactivation is aberrant from normal meiosis in some events. As Pat1 inactivation is often useful to induce S. pombe cells synchronously into meiosis, the temporal order of chromosomal events determined here will provide landmarks for the progression of meiosis downstream the Pat1 inactivation. [source] Targeted Deletion of the Sclerostin Gene in Mice Results in Increased Bone Formation and Bone Strength,,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 6 2008Xiaodong Li Abstract Introduction: Sclerosteosis is a rare high bone mass genetic disorder in humans caused by inactivating mutations in SOST, the gene encoding sclerostin. Based on these data, sclerostin has emerged as a key negative regulator of bone mass. We generated SOST knockout (KO) mice to gain a more detailed understanding of the effects of sclerostin deficiency on bone. Materials and Methods: Gene targeting was used to inactivate SOST and generate a line of SOST KO mice. Radiography, densitometry, ,CT, histomorphometry, and mechanical testing were used to characterize the impact of sclerostin deficiency on bone in male and female mice. Comparisons were made between same sex KO and wildtype (WT) mice. Results: The results for male and female SOST KO mice were similar, with differences only in the magnitude of some effects. SOST KO mice had increased radiodensity throughout the skeleton, with general skeletal morphology being normal in appearance. DXA analysis of lumbar vertebrae and whole leg showed that there was a significant increase in BMD (>50%) at both sites. ,CT analysis of femur showed that bone volume was significantly increased in both the trabecular and cortical compartments. Histomorphometry of trabecular bone revealed a significant increase in osteoblast surface and no significant change in osteoclast surface in SOST KO mice. The bone formation rate in SOST KO mice was significantly increased for trabecular bone (>9-fold) at the distal femur, as well as for the endocortical and periosteal surfaces of the femur midshaft. Mechanical testing of lumbar vertebrae and femur showed that bone strength was significantly increased at both sites in SOST KO mice. Conclusions:SOST KO mice have a high bone mass phenotype characterized by marked increases in BMD, bone volume, bone formation, and bone strength. These results show that sclerostin is a key negative regulator of a powerful, evolutionarily conserved bone formation pathway that acts on both trabecular and cortical bone. [source] PTEN: a promising pharmacological target to enhance epithelial wound healingBRITISH JOURNAL OF PHARMACOLOGY, Issue 8 2007M Zhao PI3Ks (phosphoinositide-3 kinases) produce PIP3 (phosphatidylinositol(3,4,5)-trisphosphate) which mediates signals for cell survival and proliferation. The tumour suppressor PTEN (phosphatase and tensin homologue) dephosphorylates PIP3 and is a key negative regulator of PI3K signalling. Recent research highlighted important roles for PI3K/PTEN in cell polarization and directional cell migration, pointing to a significant role for PTEN in wound healing where spatially organized tissue growth is essential. Lai et al. (in this issue of British Journal of Pharmacology) have moved a step closer in utilizing PTEN for wound healing through pharmacological inhibition. Two vanadium derivative inhibitors targeting PTEN significantly elevated the level of phosphorylated Akt (protein kinase B) and nearly doubled the wound healing rate in monolayer cultures of lung and airway epithelial cells. Damage to airway and lung epithelia underlies a wide spectrum of significant clinical conditions. With further experiments, this promising approach may find potential clinical use in situations where enhanced wound healing of pulmonary and other epithelia is important. British Journal of Pharmacology (2007) 152, 1141,1144; doi:10.1038/sj.bjp.0707503; published online 8 October 2007 [source] Modulation of drought resistance by the abscisic acid receptor PYL5 through inhibition of clade A PP2CsTHE PLANT JOURNAL, Issue 4 2009Julia Santiago Summary Abscisic acid (ABA) is a key phytohormone involved in adaption to environmental stress and regulation of plant development. Clade A protein phosphatases type 2C (PP2Cs), such as HAB1, are key negative regulators of ABA signaling in Arabidopsis. To obtain further insight into regulation of HAB1 function by ABA, we have screened for HAB1-interacting partners using a yeast two-hybrid approach. Three proteins were identified, PYL5, PYL6 and PYL8, which belong to a 14-member subfamily of the Bet v1-like superfamily. HAB1,PYL5 interaction was confirmed using BiFC and co-immunoprecipitation assays. PYL5 over-expression led to a globally enhanced response to ABA, in contrast to the opposite phenotype reported for HAB1 -over-expressing plants. F2 plants that over-expressed both HAB1 and PYL5 showed an enhanced response to ABA, indicating that PYL5 antagonizes HAB1 function. PYL5 and other members of its protein family inhibited HAB1, ABI1 and ABI2 phosphatase activity in an ABA-dependent manner. Isothermal titration calorimetry revealed saturable binding of (+)ABA to PYL5, with Kd values of 1.1 ,m or 38 nm in the absence or presence of the PP2C catalytic core of HAB1, respectively. Our work indicates that PYL5 is a cytosolic and nuclear ABA receptor that activates ABA signaling through direct inhibition of clade A PP2Cs. Moreover, we show that enhanced resistance to drought can be obtained through PYL5-mediated inhibition of clade A PP2Cs. [source] | |||||||||||||