Peroxiredoxins Play an Important Role in the Regulation of Immunity and Aging in Drosophila.

Aberrant immune responses and chronic inflammation can impose significant health risks and promote premature aging. Pro-inflammatory responses are largely mediated via reactive oxygen species (ROS) and reduction-oxidation reactions. A pivotal role in maintaining cellular redox homeostasis and the proper control of redox-sensitive signaling belongs to a family of antioxidant and redox-regulating thiol-related peroxidases designated as peroxiredoxins (Prx). Our recent studies in Drosophila have shown that Prxs play a critical role in aging and immunity. We identified two important 'hubs', the endoplasmic reticulum (ER) and mitochondria, where extracellular and intracellular stress signals are transformed into pro-inflammatory responses that are modulated by the activity of the Prxs residing in these cellular organelles. Here, we found that mitochondrial Prx activity in the intestinal epithelium is required to prevent the development of intestinal barrier dysfunction, which can drive systemic inflammation and premature aging. Using a redox-negative mutant, we demonstrated that Prx acts in a redox-dependent manner in regulating the age-related immune response. The hyperactive immune response observed in flies under-expressing mitochondrial Prxs is due to a response to abiotic signals but not to changes in the bacterial content. This hyperactive response, but not reduced lifespan phenotype, can be rescued by the ER-localized Prx.

CDC20-Mediated hnRNPU Ubiquitination Regulates Chromatin Condensation and Anti-Cancer Drug Response.

Cell division cycle 20 (CDC20) functions as a critical cell cycle regulator. It plays an important role in cancer development and drug resistance. However, the molecular mechanisms by which CDC20 regulates cellular drug response remain poorly understood. Chromatin-associated CDC20 interactome in breast cancer cells was analyzed by using affinity purification coupled with mass spectrometry. hnRNPU as a CDC20 binding partner was validated by co-immunoprecipitation and immunostaining. The molecular domain, comprising amino acid residues 461-653, on hnRNPU required for its interaction with CDC20 was identified by mapping of interactions. Co-immunoprecipitation showed that CDC20-mediated hnRNPU ubiquitination promotes its interaction with the CTCF and cohesin complex. The effects of CDC20-hnRNPU on nuclear size and chromatin condensation were investigated by analyzing DAPI and H2B-mCherry staining, respectively. The role of CDC20-hnRNPU in tumor progression and drug resistance was examined by CCK-8 cell survival and clonogenic assays. Our study indicates that CDC20-mediated ubiquitination of hnRNPU modulates chromatin condensation by regulating the interaction between hnRNPU and the CTCF-cohesin complex. Dysregulation of the CDC20-hnRNPU axis contributes to tumor progression and drug resistance.

Ductal Carcinoma In Situ of Breast: From Molecular Etiology to Therapeutic Management.

Ductal carcinoma in situ (DCIS) makes up a majority of noninvasive breast cancer cases. DCIS is a neoplastic proliferation of epithelial cells within the ductal structure of the breast. Currently, there is little known about the progression of DCIS to invasive ductal carcinoma (IDC), or the molecular etiology behind each DCIS lesion or grade. The DCIS lesions can be heterogeneous in morphology, genetics, cellular biology, and clinical behavior, posing challenges to our understanding of the molecular mechanisms by which approximately half of all DCIS lesions progress to an invasive status. New strategies that pinpoint molecular mechanisms are necessary to overcome this gap in understanding, which is a barrier to more targeted therapy. In this review, we will discuss the etiological factors associated with DCIS, as well as the complexity of each nuclear grade lesion. Moreover, we will discuss the possible molecular features that lead to progression of DCIS to IDC. We will highlight current therapeutic management and areas for improvement.

ARID1 proteins: from transcriptional and post-translational regulation to carcinogenesis and potential therapeutics.

The ARID1 proteins are mutually exclusive subunits of the BRG1/BRM-associated factor (BAF) complexes that play an important role in chromatin remodeling and regulate many fundamental cell functions. The role of ARID1s is well defined as a tumor-suppressive. The cancer cells evolve different mechanisms to downregulate ARID1s and inactivate their functions. ARID1s are frequently mutated in human cancer. The recent findings of ARID1A/B downregulation at transcriptional and translational levels along with their low levels in human cancers indicate the significance of regulatory mechanisms of ARID1s in cancers. In this review, we present the current knowledge on the regulation and alterations of ARID1 protein expression in human cancers and indicate the importance of regulators of ARID1s as a prognostic marker and in potential therapeutic strategies.

Mitochondrial Redox Signaling Is Critical to the Normal Functioning of the Neuronal System.

Mitochondrial dysfunction often leads to neurodegeneration and is considered one of the main causes of neurological disorders, such as Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and other age-related diseases. Mitochondrial dysfunction is tightly linked to oxidative stress and accumulating evidence suggests the association between oxidative stress and neurological disorders. However, there is insufficient knowledge about the role of pro-oxidative shift in cellular redox and impairment of redox-sensitive signaling in the development of neurodegenerative pathological conditions. To gain a more complete understanding of the relationship between mitochondria, redox status, and neurodegenerative disorders, we investigated the effect of mitochondrial thiol-dependent peroxidases, peroxiredoxins (Prxs), on the physiological characteristics of flies, which change with pathologies such as PD, ALS and during aging. We previously found that through their ability to sense changes in redox and regulate redox-sensitive signaling, Prxs play a critical role in maintaining global thiol homeostasis, preventing age-related apoptosis and chronic activation of the immune response. We also found that the phenotype of flies under-expressing Prxs in mitochondria shares many characteristics with the phenotype of Drosophila models of neurological disorders such as ALS, including impaired locomotor activity and compromised redox balance. Here, we expanded the study and found that under-expression of mitochondrial Prxs leads to behavioral changes associated with neural function, including locomotor ability, sleep-wake behavior, and temperature-sensitive paralysis. We also found that under-expression of mitochondrial Prxs with a motor-neuron-specific driver, D42-GAL4, was a determining factor in the development of the phenotype of shortened lifespan and impaired motor activity in flies. The results of the study suggest a causal link between mitochondrial Prx activity and the development of neurological disorders and pre-mature aging.

Malignant cell-specific pro-tumorigenic role of type I interferon receptor in breast cancers.

Within the microenvironment of solid tumors, stress associated with deficit of nutrients and oxygen as well as tumor-derived factors triggers the phosphorylation-dependent degradation of the IFNAR1 chain of type I interferon (IFN1) receptor and ensuing suppression of the IFN1 pathway. Here we sought to examine the importance of these events in malignant mammary cells. Expression of non-degradable IFNAR1S526A mutant in mouse mammary adenocarcinoma cells stimulated the IFN1 pathway yet did not affect growth of these cells in vitro or ability to form subcutaneous tumors in the syngeneic mice. Remarkably, these cells exhibited a notably accelerated growth when transplanted orthotopically into mammary glands. Importantly, in human patients with either ER+ or ER- breast cancers, high levels of IFNAR1 were associated with poor prognosis. We discuss the putative mechanisms underlying the pro-tumorigenic role of IFNAR1 in malignant breast cells.

Mitochondrial peroxiredoxins are essential in regulating the relationship between Drosophila immunity and aging.

Previously, we have shown that flies under-expressing the two mitochondrial peroxiredoxins (Prxs), dPrx3 and dPrx5, display increases in tissue-specific apoptosis and dramatically shortened life span, associated with a redox crisis, manifested as changes in GSH:GSSG and accumulation of protein mixed disulfides. To identify specific pathways responsible for the observed biological effects, we performed a transcriptome analysis. Functional clustering revealed a prominent group enriched for immunity-related genes, including a considerable number of NF-kB-dependent antimicrobial peptides (AMP) that are up-regulated in the Prx double mutant. Using qRT-PCR analysis we determined that the age-dependent changes in AMP levels in mutant flies were similar to those observed in controls when scaled to percentage of life span. To further clarify the role of Prx-dependent mitochondrial signaling, we expressed different forms of dPrx5, which unlike the uniquely mitochondrial dPrx3 is found in multiple subcellular compartments, including mitochondrion, nucleus and cytosol. Ectopic expression of dPrx5 in mitochondria but not nucleus or cytosol partially extended longevity under normal or oxidative stress conditions while complete restoration of life span occurred when all three forms of dPrx5 were expressed from the wild type dPrx5 transgene. When dPrx5 was expressed in mitochondria or in all three compartments, it substantially delayed the development of hyperactive immunity while expression of cytosolic or nuclear forms had no effect on the immune phenotype. The data suggest a critical role of mitochondria in development of chronic activation of the immune response triggered by impaired redox control.