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Tumor Suppressor Loss and Mitotic Checkpoint Overactivation as a Crossroads to Cancer

机译：肿瘤抑制因子丢失和有丝分裂检查点过度活跃作为癌症的十字路口

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The current proposal aims to investigate the relationship between loss of classic tumor suppressor mechanisms of the Rb pathway and chromosomal instability (CIN) as controlled by the Spindle Assembly Checkpoint (SAC). Deregulation of the SAC as a result of overexpression of the Mad2 gene has already been shown to lead to the formation of a variety of solid tumors, among them breast cancer. As cells proceed from G1 to S, pocket proteins of the Rb family are inhibited and E2F factors are able to upregulate the expression of downstream targets, among them Mad2. The Rb pathway is frequently deregulated in human tumors and, in animal and cell culture models, loss of Rb function leads to high levels of Mad2. These findings lead to our hypothesis that inhibition of pocket protein function, by upregulating Mad2 levels, can drive CIN as a result of overactivation of the SAC. Here we present evidence that upregulation of Mad2 is necessary for the chromosomal instability seen after inhibition of the Rb pathway. Furthermore, we show that Mad2 normalization markedly decreases the growth of subcutaneously implanted transformed TKO fibroblasts and that, in an in vivo model of breast cancer triggered by inhibition of the Rb pathway, Mad2 heterozygosity prolongs tumor onset and leads to a shift towards a less aggressive, more differentiated tumor phenotype. These results reinforce the notion that chromosomal instability is an intricate part of tumor development and can result directly from the inhibition of a tumor suppressor pathway. We are currently investigating whether later events in the tumorigenic process are also affected by chromosomal instability.

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