Critical Step In Induction Research Articles

QSER1 preserves the suppressive status of the pro-apoptotic genes to prevent apoptosis.

Activation of the pro-apoptotic genes by the p53 family is a critical step in induction of apoptosis. However, the molecular signaling underlying their suppression remains largely unknown. Here, we report a general role of QSER1 in preventing apoptosis. QSER1 is widely up-regulated in multiple cancers, and its up-regulation correlates with poor clinic outcomes. QSER1 knockdown significantly promotes apoptosis in both p53 wild type and mutant cancer cells. Interestingly, we show that QSER1 and p53 occupy distinct cis-regulatory regions in a common subset of the pro-apoptotic genes, and function antagonistically to maintain their proper expression. Furthermore, we identify a key regulatory DNA element named QSER1 binding site in PUMA (QBP). Deletion of QBP de-represses PUMA and induces apoptosis. Mechanistically, QSER1 functions together with SIN3A to suppress PUMA in a p53-dependent and -independent manner, suggesting that QSER1 inhibition might be a potential therapeutic strategy to induce apoptosis in cancers.

Coenzyme Q blocks biochemical but not receptor-mediated apoptosis by increasing mitochondrial antioxidant protection

Generation of free radicals is often associated with the induction and progression of apoptosis. Therefore, antioxidants can prove anti-apoptotic, and can help to elucidate specific apoptotic pathways. Here we studied whether coenzyme Q, present in membranes in reduced (ubiquinol) or oxidised (ubiquinone) forms, can affect apoptosis induced by various stimuli. Exposure of Jurkat cells to α-tocopheryl succinate (α-TOS), hydrogen peroxide, anti-Fas IgM or TRAIL led to induction of apoptosis. Cell death due to the chemical agents was suppressed in cells enriched with the reduced form of coenzyme Q. However, coenzyme Q did not block cell death induced by the immunological agents. Ubiquinol-10 inhibited reactive oxygen species (ROS) generation in cells exposed to α-TOS, and a mitochondrially targeted coenzyme Q analogue also blocked apoptosis triggered by α-TOS or hydrogen peroxide. Therefore, it is plausible that ubiquinol-10 protects cells from chemically-induced apoptosis by acting as an antioxidant in mitochondria. Our results also indicate that generation of free radicals may not be a critical step in induction of apoptosis by immunological agents.

Proliferation of Maximally Activated Antigen-Primed Cells: A Computer Simulation

Abstract Most reported models of formation of antibody or induction of tolerance require interaction between antigen and an antibody-like receptor on the surface of a potentially immunocompetent cell as a critical step for induction or suppression of the immune response. In the simplest situation, where interaction is between identical antigenic fragments and identical receptor units, the nature of the immune response must depend upon the geometric distribution of bound receptors on the cell. Considerations such as these led to formulation of a precise, quantitative model of the process by which the immune response is activated. The availability of such a model made possible computer simulation of the division of an activated cell to form a clone. In this simulation, if activated cells were allowed to divide until the number of antigen-bound receptor sites fell below various threshold values, the frequency distribution of progeny as a function of bound sites was biphasic for certain narrow ranges of these thresholds. The two populations so defined, which differed in the number of divisions they had undergone and the number of bound receptors they possessed, might represent a pool of end-stage antibody-producing cells and a pool of intermediate cells that have immunologic memory. A major consequence of this interpretation was restriction of heterogeneity in the secondary response.