Sporadic basal-like cancers (BLC) are a distinct class of human breast cancers that are phenotypically similar to BRCA1-associated cancers. Like BRCA1-deficient tumors, most BLC lack markers of a normal inactive X chromosome (Xi). Duplication of the active X chromosome and loss of Xi characterized almost half of BLC cases tested. Others contained biparental but nonheterochromatinized X chromosomes or gains of X chromosomal DNA. These abnormalities did not lead to a global increase in X chromosome transcription but were associated with overexpression of a small subset of X chromosomal genes. Other, equally aneuploid, but non-BLC rarely displayed these X chromosome abnormalities. These results suggest that X chromosome abnormalities contribute to the pathogenesis of BLC, both inherited and sporadic.
There are currently two distinct models proposed to explain why both MDM2 and MDMX are required in p53 control, with a key difference centered on whether these two p53 inhibitors work together or independently. To test these two competing models, we generated knockin mice expressing a point mutation MDMX mutant (C462A) that is defective in MDM2 binding. This approach allowed a targeted disassociation of the MDM2/MDMX heterocomplex without affecting the ability of MDMX to bind to p53, and while leaving the MDM2 protein itself completely untouched. Significantly, Mdmx C462A/C462A homozygous mice died at approximately day 9.5 of embryonic development, as the result of a combination of apoptosis and decreased cell proliferation, as shown by TUNEL and BrdU incorporation assays, respectively. Interestingly, even though the MDMX mutant protein abundance was found slightly elevated in the Mdmx C462A/C462A homozygous embryos, both the abundance and activity of p53 were markedly increased. A p53-dependent death was demonstrated by the finding that concomitant deletion of p53 completely rescued the embryonic lethality in Mdmx C462A/C462A homozygous mice. Our data demonstrate that MDM2 and MDMX function as an integral complex in p53 control, providing insights into the nonredundant nature of the function of MDM2 and MDMX.knockin mouse model | p53 regulation U nder normal physiological conditions, wild-type p53 protein levels must be kept low owing to its growth-inhibitory activities, and this control is mainly modulated via regulation of p53 protein stability. Although a number of different regulators have been reported to be involved in this protein regulation, MDM2 has been shown to be the principal player in control of p53 turnover (1). MDM2 primarily functions as an E3 ubiquitin ligase targeting p53 for ubiquitination and subsequent degradation. At the same time, p53 induces the expression of the Mdm2 gene, forming a negative feedback loop (1). The importance of MDM2 in p53 control is highlighted by the finding that Mdm2 knockout results in p53-dependent embryonic lethality in mice (2, 3).MDMX (also known as MDM4), which was originally isolated as a novel p53-interacting protein, shares substantial structural homology with MDM2 (4, 5). The highest sequence similarity between MDM2 and MDMX lies at the N terminus and contains a p53-binding domain, and the two also share high sequence homology in a RING-finger domain, a region that mediates the association between MDMX and MDM2 (6,7). Genetic studies have demonstrated that like MDM2, MDMX is another essential negative regulator of p53 (8-10). Although it remains unclear why both MDM2 and MDMX are required for p53 control, a model has been proposed that these two proteins function independently. On the basis of the fact that unlike MDM2, MDMX lacks an intrinsic ubiquitin E3 ligase activity, it has been proposed that MDMX inhibits p53 chiefly by binding to the p53 transactivation domain and antagonizing p53 transcription activity, whereas MDM2 inactivates p53 primarily by wo...
Telomeres cap the ends of eukaryotic chromosomes and prevent them from being recognized as DNA breaks. We have shown that certain DNA damage responses induced during senescence and, at times of telomere uncapping, also can be induced by treatment of cells with small DNA oligonucleotides homologous to the telomere 3 single-strand overhang (T-oligos), implicating this overhang in generation of these telomere-based damage responses. Here, we show that T-oligo-treated fibroblasts contain ␥H2AX foci and that these foci colocalize with telomeres. T-oligos with nuclease-resistant 3 ends are inactive, suggesting that a nuclease initiates T-oligo responses. We therefore examined WRN, a 3 3 5 exonuclease and helicase mutated in Werner syndrome, a disorder characterized by aberrant telomere maintenance, premature aging, chromosomal rearrangements, and predisposition to malignancy. Normal fibroblasts and U20S osteosarcoma cells rendered deficient in WRN showed reduced phosphorylation of p53 and histone H2AX in response to T-oligo treatment. Together, these data demonstrate a role for WRN in processing of telomeric DNA and subsequent activation of DNA damage responses. The T-oligo model helps define the role of WRN in telomere maintenance and initiation of DNA damage responses after telomere disruption.exonuclease ͉ ␥-H2AX foci ͉ Werner syndrome ͉ senescence ͉ oligonucleotide
Chemoresistance contributes to cancer relapse and increased mortality in a variety of cancer types, raising a pressing need to better understand the underlying mechanism. MUC1 is abnormally overexpressed in numerous carcinomas and associated with poor prognosis. However, the functional significance of MUC1 in chemoresistance has not been fully elucidated. Here, we showed that MUC1 expression was considerably induced in cells that had acquired chemoresistance at both transcriptional and post-translational levels. Using gain- and loss-of function approaches, we demonstrated a critical role of MUC1 in induction of drug resistance. Through stimulation of EGFR activation and nuclear translocation, MUC1 increased the expression of ATP-binding cassette transporter B1 (ABCB1). Remarkably, targeted suppression of EGFR or ABCB1 by both shRNAs and inhibitors effectively reversed chemoresistance. Moreover, co-administration of the inhibitors of MUC1–EGFR–ABCB1 with paclitaxel significantly blocked not only tumor growth but also relapse in xenograft mouse model. Our data collectively support a model in which MUC1 induces acquired chemotherapy resistance by upregulating ABCB1 in an EGFR-dependent manner, providing a novel molecular basis of using the EGFR inhibitor in MUC1-positive cancers to prevent chemotherapy resistance.
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