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Unlike other antiapoptotic Bcl-2 family members, Mcl-1 also mediates resistance to cancer therapy by uniquely inhibiting chemotherapy-induced senescence (CIS). In general, Bcl-2 family members regulate apoptosis at the level of the mitochondria through a common prosurvival binding groove. Through mutagenesis, we determined that Mcl-1 can inhibit CIS even in the absence of its apoptotically important mitochondrion-localizing domains. This finding prompted us to generate a series of Mcl-1 deletion mutants from both the N and C termini of the protein, including one that contained a deletion of all of the Bcl-2 homology domains, none of which impacted anti-CIS capabilities. Through subsequent structure-function analyses of Mcl-1, we identified a previously uncharacterized loop domain responsible for the anti-CIS activity of Mcl-1. The importance of the loop domain was confirmed in multiple tumor types, two in vivo models of senescence, and by demonstrating that a peptide mimetic of the loop domain can effectively inhibit the anti-CIS function of Mcl-1. The results from our studies appear to be highly translatable because we discerned an inverse relationship between the expression of Mcl-1 and of various senescence markers in cancerous human tissues. In summary, our findings regarding the unique structural properties of Mcl-1 provide new approaches for targeted cancer therapy.  相似文献   
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Unequal absorption of photons between photosystems I and II, and between bundle-sheath and mesophyll cells, are likely to affect the efficiency of the CO2-concentrating mechanism in C4 plants. Under steady-state conditions, it is expected that the biochemical distribution of energy (ATP and NADPH) and photosynthetic metabolite concentrations will adjust to maintain the efficiency of C4 photosynthesis through the coordination of the C3 (Calvin-Benson-Bassham) and C4 (CO2 pump) cycles. However, under transient conditions, changes in light quality will likely alter the coordination of the C3 and C4 cycles, influencing rates of CO2 assimilation and decreasing the efficiency of the CO2-concentrating mechanism. To test these hypotheses, we measured leaf gas exchange, leaf discrimination, chlorophyll fluorescence, electrochromatic shift, photosynthetic metabolite pools, and chloroplast movement in maize (Zea mays) and Miscanthus × giganteus following transitional changes in light quality. In both species, the rate of net CO2 assimilation responded quickly to changes in light treatments, with lower rates of net CO2 assimilation under blue light compared with red, green, and blue light, red light, and green light. Under steady state, the efficiency of CO2-concentrating mechanisms was similar; however, transient changes affected the coordination of C3 and C4 cycles in M. giganteus but to a lesser extent in maize. The species differences in the ability to coordinate the activities of C3 and C4 cycles appear to be related to differences in the response of cyclic electron flux around photosystem I and potentially chloroplast rearrangement in response to changes in light quality.The CO2-concentrating mechanism in C4 plants reduces the carbon lost through the photorespiratory pathway by limiting the oxygenation of ribulose-1,5-bisphosphate (RuBP) by the enzyme Rubisco (Brown and Smith, 1972; Sage, 1999). Through the compartmentalization of the C4 cycle in the mesophyll cells and the C3 cycle in the bundle-sheath cells (Hatch and Slack, 1966), C4 plants suppress RuBP oxygenation by generating a high CO2 partial pressure around Rubisco (Furbank and Hatch, 1987). To maintain high photosynthetic rates and efficient light energy utilization, the metabolic flux through the C3 and C4 cycles must be coordinated. However, coordination of the C3 and C4 cycles is likely disrupted due to rapid changes in environmental conditions, particularly changes in light availability (Evans et al., 2007; Tazoe et al., 2008).Spatial and temporal variations in light environments, including both light quantity and quality, are expected to alter the coordination of the C3 and C4 cycles. For example, it has been suggested that the coordination of C3 and C4 cycles is altered by changes in light intensity (Henderson et al., 1992; Cousins et al., 2006; Tazoe et al., 2006, 2008; Kromdijk et al., 2008, 2010; Pengelly et al., 2010). However, more recent publications indicate that some of the proposed light sensitivity of the CO2-concentrating mechanisms in C4 plants can be attributed to oversimplifications of leaf models of carbon isotope discrimination (Δ13C), in particular, errors in estimates of bundle-sheath CO2 partial pressure and omissions of respiratory fractionation (Ubierna et al., 2011, 2013). Alternatively, there is little information on the effects of light quality on the coordination of C3 and C4 cycle activities and the subsequent impact on net rate of CO2 assimilation (Anet).In C3 plants, Anet is reduced under blue light compared with red or green light (Evans and Vogelmann, 2003; Loreto et al., 2009). This was attributed to differences in absorbance and wavelength-dependent differences in light penetration into leaves, where red and green light penetrate farther into leaves compared with blue light (Vogelmann and Evans, 2002; Evans and Vogelmann, 2003). Differences in light quality penetration into a leaf are likely to have profound impacts on C4 photosynthesis, because the C4 photosynthetic pathway requires the metabolic coordination of the mesophyll C4 cycle and the bundle-sheath C3 cycle. Indeed, Evans et al. (2007) observed a 50% reduction in the rate of CO2 assimilation in Flaveria bidentis under blue light relative to white light at a light intensity of 350 µmol quanta m−2 s−1. This was attributed to poor penetration of blue light into the bundle-sheath cells and subsequent insufficient production of ATP in the bundle-sheath cells to match the rates of mesophyll cell CO2 pumping (Evans et al., 2007). Recently, Sun et al. (2012) observed similar low rates of steady-state CO2 assimilation under blue light relative to red, green, and blue light (RGB), red light, and green light at a constant light intensity of 900 µmol quanta m−2 s−1.Because the light penetration into a leaf depends on light quality, with blue light penetrating the least, this potentially results in changes in the energy available for carboxylation reactions in the bundle-sheath (C3 cycle) and mesophyll (C4 cycle) cells. Changes in the balance of energy driving the C3 and C4 cycles can alter the efficiency of the CO2-concentrating mechanisms, often represented by leakiness (ϕ), the fraction of CO2 that is pumped into the bundle-sheath cells that subsequently leaks back out (Evans et al., 2007). Unfortunately, ϕ cannot be measured directly, but it can be estimated through the combined measured and modeled values of Δ13C (Farquhar, 1983). Using measurements of Δ13C, it has been demonstrated that under steady-state conditions, changes in light quality do not affect ϕ (Sun et al., 2012); however, it remains unknown if ϕ is also constant during the transitions between different light qualities. In fact, sudden changes of light quality could temporally alter the coordination of the C3 and C4 cycles.To understand the effects of light quality on C4 photosynthesis and the coordination of the activities of C3 and C4 cycles, we measured transitional changes in leaf gas exchange and Δ13C under RGB and broad-spectrum red, green, and blue light in the NADP-malic enzyme C4 plants maize (Zea mays) and Miscanthus × giganteus. Leaf gas exchange and Δ13C measurements were used to estimate ϕ using the complete model of C4 leaf Δ13C (Farquhar, 1983; Farquhar and Cernusak, 2012). Additionally, we measured photosynthetic metabolite pools, Rubisco activation state, chloroplast movement, and rates of linear versus cyclic electron flow during rapid transitions from red to blue light and blue to red light. We hypothesized that the limited penetration of blue light into the leaf would result in insufficient production of ATP in the bundle-sheath cells to match the rate of mesophyll cell CO2 pumping. We predicted that rapid changes in light quality would affect the coordination of the C3 and C4 cycles and cause an increase in ϕ, but this would equilibrate as leaf metabolism reached a new steady-state condition.  相似文献   
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Vascular smooth muscle cells (VSMCs) are exposed to mechanical cyclic stretch in vivo, which play important roles in maintenance of vascular homeostasis and regulation of pathological vascular remodeling. Reversible protein phosphorylation is crucial for intracellular signaling transduction. However, the dynamic phosphorylated profile induced by cyclic stretch in VSMCs is still unclear. Using the stable isotope labeling by amino acid in cell culture, VSMCs were labeled and exposed to 10% physiological cyclic stretch in vitro at 1.25 Hz for 0 min, 15 min, 30 min, 1 h and 6 h, respectively. Using TiO2 beads and liquid chromatography tandem mass spectrometry, the temporal phosphoproteomic profiles in response to cyclic stretch were then detected. Bioinformatics analysis including fuzzy c-means clustering, functional classifications, and Ingenuity Pathway Analysis were applied to further reveal the potential mechanotranduction networks. The results indicated that protein kinase C (PKCs) family, Rho-associated coiled-coil containing protein kinase 1 (ROCK1) and Akt may participate in cyclic-stretch induced VSMC functions. Cyclic stretch repressed the expression of ROCK1, while it had no significant effect on the phosphorylation of PKCα/βII, PKCζ/λ and PKCδ/θ. PKCθ was activated first at short time-phase (15 min and 30 min), and again at long time-phase (6 h, 12 h and 24 h). The activation of p-PKCμ was immediate and short-term, similar to p-Akt. Our present in vitro work hence revealed that cyclic stretch activates complex mechanotransduction networks, suggesting that novel mechanoresponsive molecules, i.e., PKCθ, PKCμ, and ROCK1, may participate in the mechanotransduction and modulation VSMC functions.  相似文献   
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Autophagy, the process by which proteins or organelles are engulfed by autophagosomes and delivered for vacuolar/lysosomal degradation, is induced to ensure survival under starvation and other stresses. A selective autophagic pathway for 60S ribosomal subunits elicited by nitrogen starvation in yeast—ribophagy—was recently described and requires the Ubp3-Bre5 deubiquitylating enzyme. This discovery implied that an E3 ligases act upstream, whether inhibiting the process or providing an initial required signal. In this paper, we show that Ltn1/Rkr1, a 60S ribosome-associated E3 implicated in translational surveillance, acts as an inhibitor of 60S ribosomal subunit ribophagy and is antagonized by Ubp3. The ribosomal protein Rpl25 is a relevant target. Its ubiquitylation is Ltn1 dependent and Ubp3 reversed, and mutation of its ubiquitylation site rendered ribophagy less dependent on Ubp3. Consistently, the expression of Ltn1—but not Ubp3—rapidly decreased after starvation, presumably to allow ribophagy to proceed. Thus, Ltn1 and Ubp3-Bre5 likely contribute to adapt ribophagy activity to both nutrient supply and protein translation.  相似文献   
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Meiotic crossovers (COs) are crucial for ensuring accurate homologous chromosome segregation during meiosis I. Because the double-strand breaks (DSBs) that initiate meiotic recombination greatly outnumber eventual COs, this process requires exquisite regulation to narrow down the pool of DSB intermediates that may form COs. In this paper, we identify a cyclin-related protein, CNTD1, as a critical mediator of this process. Disruption of Cntd1 results in failure to localize CO-specific factors MutLγ and HEI10 at designated CO sites and also leads to prolonged high levels of pre-CO intermediates marked by MutSγ and RNF212. These data show that maturation of COs is intimately coupled to deselection of excess pre-CO sites to yield a limited number of COs and that CNTD1 coordinates these processes by regulating the association between the RING finger proteins HEI10 and RNF212 and components of the CO machinery.  相似文献   
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The absorption of phospholipid may improve the fluidity of membrane and enzyme activities. Phospholipids also play a role in promoting Caveolae formation and membrane synthesis. Caveolin-1 has a significant effect on signaling pathways involved in regulating cell proliferation and stress responsiveness. Thus, we can speculate that Caveolin-1 could affect the sense of environmental stress. We use Chang liver cell line to investigate the ability of Caveolin-1 to modulate the cellular response to ethanol injury. Caveolin-1 downregulate cells (Cav-1?/?) were established by stable transfecting with psiRNA-CAV1 plasmids, which were more sensitive to toxic effects of ethanol than the untransfected parental cells (WT). Releasing of ALT and electric conductivity were changed significantly in Cav-1?/? cells compared with WT. Caveolin-1 gene silencing could obviously down-regulate the activities of protein kinase C-α (PKC-α) and phospho-p42/44 MAP kinase, indicating cell proliferation and self-repairing abilities were inhibited. However, the levels of Caveolin-1 and PKC-α were increased by phosphatidylcholine administration. The results indicated that the inhibition of lipid peroxidation by phosphatidylcholine could lead to the prevention of membrane disruption, which closely correlated with the level of Caveolin-1. Since the protective effects of phosphatidylcholine against ethanol-induced lipid peroxidation might be regulated by phospholipid-PKC-α signaling pathway, related with Caveolin-1, the potential effects of phosphatidylcholine on membranes need to be verified.  相似文献   
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Frugivorous and nectarivorous bats rely largely on hepatic glycogenesis and glycogenolysis for postprandial blood glucose disposal and maintenance of glucose homeostasis during short time starvation, respectively. The glycogen synthase 2 encoded by the Gys2 gene plays a critical role in liver glycogen synthesis. To test whether the Gys2 gene has undergone adaptive evolution in bats with carbohydrate-rich diets in relation to their insect-eating sister taxa, we sequenced the coding region of the Gys2 gene in a number of bat species, including three Old World fruit bats (OWFBs) (Pteropodidae) and two New World fruit bats (NWFBs) (Phyllostomidae). Our results showed that the Gys2 coding sequences are highly conserved across all bat species we examined, and no evidence of positive selection was detected in the ancestral branches leading to OWFBs and NWFBs. Our explicit convergence test showed that posterior probabilities of convergence between several branches of OWFBs, and the NWFBs were markedly higher than that of divergence. Three parallel amino acid substitutions (Q72H, K371Q, and E666D) were detected among branches of OWFBs and NWFBs. Tests for parallel evolution showed that two parallel substitutions (Q72H and E666D) were driven by natural selection, while the K371Q was more likely to be fixed randomly. Thus, our results suggested that the Gys2 gene has undergone parallel evolution on amino acid level between OWFBs and NWFBs in relation to their carbohydrate metabolism.  相似文献   
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