For all other subsequent experiments, the same protocol was followed unless otherwise specified

For all other subsequent experiments, the same protocol was followed unless otherwise specified

so worth noting a study by Young et al., in which acute inactivation of pVHL the ubiquitin ligase part of the proteasome that downregulates Hif1a under normoxic conditions- caused a senescent-like phenotype in MEFs, with overexpression of p27, another cyclin-kinase inhibitor. This phenotype is independent of p53 and Hif1a, even though Hif1a and Glut1 proteins were accumulated in these cells. Complete loss of SdhD induces overexpression of the glucose transporter, Glut1, in our cultured cells, which indicates 10224110 a metabolic switch towards glycolysis. This change in gene expression seems to be mediated by a “pseudo-hypoxic”response in which Hif1a plays a central regulatory role. However, it is conceivable that, even though the up-regulation of Glut1 may be caused in 10224109 the first instance by activated Hif1a, the complete loss of mitochondrial function will eventually force the cells to undergo a glycolytic switch with gene expression changes independent of Hif1a. Indeed, a general and rapid Hif-mediated “pseudo-hypoxic”response A-83-01 cannot be addressed from the SDHDESR model, as some bona fide Hif-target genes are not affected in a general and consistent manner. Our cell culture experiments also showed that Hif1a stabilization is transient, which possibly makes difficult to detect this protein in SDHD-ESR p21WAF1/Cip1 Overexpression in a SdhD Mouse Mutant tissues after tamoxifen administration. In this regard, it has been demonstrated that reactivation of PHDs takes place upon sustained hypoxia. Although the same could happen in response to SdhD deficiency, a marginal contribution of Hif1a to the observed phenotypes cannot be ruled out. Indeed, the microarray analysis of SDHD-ESR tissues did not show a general gene expression profile responsive to hypoxia. Finally, it is noteworthy that we also did not observe any evidence of “pseudo-hypoxia”- driven changes in gene expression in either partially SdhD-deficient heterozygous tissues or in derivative cells with the same phenotype. Taken together, our data suggest that a pathogenic role for SdhD-mutation-induced Hif1a accumulation cannot be definitively established. Instead, it could play an important role in tumor progression once it has already been formed. One striking issue regarding tumors caused by mutations in MCII or associated proteins concerns tissue specificity. Although in recent years this has been partially resolved by the fact that Sdhmutation-related tumors are found in other organs, there is a preferential trend for these types of tumor to arise in paraganglionic system-derived tissues. It has been proposed that an intrinsic ability of these organs to detect oxygen might underlie a predisposition to form tumors. However, other biological characteristics could be equally relevant. Thus, the difference in gene expression changes between the adrenal medulla and kidney found in our study indicates that these tissues respond differently to SdhD deletion. In the adrenal medulla, a response pointing towards inhibition of the inflammatory response and immune surveillance is elicited, with changes in the expression of many chemokines, cytokines, and their receptors. The kidney, however, responds in a more “predictable”manner, with many metabolic readjustments promoting cell viability and survival. The physiological relevance of these changes will be explored in future work. Conclusions The identification of p21WAF1/Cip1 as one molecule that responds in a general manner to complete SdhD deletionso worth noting a study by Young et al., in which acute inactivation of pVHL the ubiquitin ligase part of the proteasome that downregulates Hif1a under normoxic conditions- caused a senescent-like phenotype in MEFs, with overexpression of p27, another cyclin-kinase inhibitor. This phenotype is independent of p53 and Hif1a, even though Hif1a and Glut1 proteins were accumulated in these cells. Complete loss of SdhD induces overexpression of the glucose transporter, Glut1, in our cultured cells, which indicates a metabolic switch towards glycolysis. This change in gene expression seems to be mediated by a “pseudo-hypoxic”response in which Hif1a plays a central regulatory role. However, it is conceivable that, even though the up-regulation of Glut1 10354404 may be caused in the first instance by activated Hif1a, the complete loss of mitochondrial function will eventually force the cells to undergo a glycolytic switch with gene expression changes independent of Hif1a. Indeed, a general and rapid Hif-mediated “pseudo-hypoxic”response cannot be addressed from the SDHDESR model, as some bona fide Hif-target genes are not affected in a general and consistent manner. Our cell culture experiments also showed that Hif1a stabilization is transient, which possibly makes difficult to detect this protein in SDHD-ESR p21WAF1/Cip1 Overexpression in a SdhD Mouse Mutant tissues after tamoxifen administration. In this regard, it has been demonstrated that reactivation of PHDs takes place upon sustained hypoxia. Although the same could happen in response to SdhD deficiency, a marginal contribution of Hif1a to the observed phenotypes cannot be ruled out. Indeed, the microarray analysis of SDHD-ESR tissues did not show a general gene expression profile responsive to hypoxia. Finally, it is noteworthy that we also did not observe any evidence of “pseudo-hypoxia”- driven changes in gene expression in either partially SdhD-deficient heterozygous tissues or in derivative cells with the same phenotype. Taken together, our data suggest that a pathogenic role for SdhD-mutation-induced Hif1a accumulation cannot be definitively established. Instead, it could play an important role in tumor progression once it has already been formed. One striking issue regarding tumors caused by mutations in MCII or associated proteins concerns tissue specificity. Although in recent years this has been partially resolved by the fact that Sdhmutation-related tumors are found in other organs, there is a preferential trend for these types of tumor to arise in paraganglionic system-derived tissues. It has been proposed that an intrinsic ability of these organs to detect oxygen might underlie a predisposition to form tumors. However, other biological characteristics could be equally relevant. Thus, the difference in gene expression changes between the adrenal medulla and kidney found in our study indicates that these tissues respond differently to SdhD deletion. In the adrenal medulla, a response pointing towards inhibition of the inflammatory response and immune surveillance is elicited, with changes in the expression of many chemokines, cytokines, and their receptors. The kidney, however, responds 18753409 in a more “predictable”manner, with many metabolic readjustments promoting cell viability and survival. The physiological relevance of these changes will be explored in future work. Conclusions The identification of p21WAF1/Cip1 as one molecule that responds in a general manner to complete SdhD deletion

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