TEOSINTE BRANCHED1-CYCLOIDEA-PROLIFERATING CELL FACTOR1 (TCP) transcription factors participate in plant developmental processes associated with cell proliferation and growth. Most members of class I, one of the two classes that compose the family, have a conserved cysteine at position 20 (Cys-20) of the TCP DNA-binding and dimerization domain. We show that Arabidopsis (Arabidopsis thaliana) class I proteins with Cys-20 are sensitive to redox conditions, since their DNAbinding activity is inhibited after incubation with the oxidants diamide, oxidized glutathione, or hydrogen peroxide or with nitric oxide-producing agents. Inhibition can be reversed by treatment with the reductants dithiothreitol or reduced glutathione or by incubation with the thioredoxin/thioredoxin reductase system. Mutation of Cys-20 in the class I protein TCP15 abolished its redox sensitivity. Under oxidizing conditions, covalently linked dimers were formed, suggesting that inactivation is associated with the formation of intermolecular disulfide bonds. Inhibition of class I TCP protein activity was also observed in vivo, in yeast (Saccharomyces cerevisiae) cells expressing TCP proteins and in plants after treatment with redox agents. This inhibition was correlated with modifications in the expression of the downstream CUC1 gene in plants. Modeling studies indicated that Cys-20 is located at the dimer interface near the DNA-binding surface. This places this residue in the correct orientation for intermolecular disulfide bond formation and explains the sensitivity of DNA binding to the oxidation of Cys-20. The redox properties of Cys-20 and the observed effects of cellular redox agents both in vitro and in vivo suggest that class I TCP protein action is under redox control in plants.TCP transcription factors constitute a family of plant developmental regulators (Martín-Trillo and Cubas, 2010;Uberti Manassero et al., 2013). The name of the family stands for the three first characterized members: TEOSINTE BRANCHED1, CYCLOIDEA, and PRO-LIFERATING CELL FACTOR1 (Cubas et al., 1999). These factors bind DNA through the TCP domain, a conserved region of approximately 60 amino acids that also participates in protein dimerization. The TCP domain contains a basic N-terminal region involved in DNA recognition, followed by a helix-loop-helix (HLH) motif similar to the one present in basic helix-loop-helix (bHLH) transcription factors (Aggarwal et al., 2010;Martín-Trillo and Cubas, 2010). Target sites recognized by TCP proteins are different from those bound by bHLH proteins (Kosugi and Ohashi, 2002;Viola et al., 2012). This is probably due to the fact that the respective basic regions differ markedly in composition and structure. Based on sequence homology, two main classes of TCP domains can be described. Class II proteins affect leaf and petal development and also influence shoot branching, among other processes

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Understanding the mechanism of metastatic dissemination is crucial for the rational design of novel therapeutics. The secreted protein acidic and rich in cysteine (SPARC) is a matricellular glycoprotein which has been extensively associated with human breast cancer aggressiveness although the underlying mechanisms are still unclear. Here, shRNA-mediated SPARC knockdown greatly reduced primary tumor growth and completely abolished lung colonization of murine 4T1 and LM3 breast malignant cells implanted in syngeneic BALB/c mice. A comprehensive study including global transcriptomic analysis followed by biological validations confirmed that SPARC induces primary tumor growth by enhancing cell cycle and by promoting a COX-2-mediated expansion of myeloid-derived suppressor cells (MDSC). The role of SPARC in metastasis involved a COX-2-independent enhancement of cell disengagement from the primary tumor and adherence to the lungs that fostered metastasis implantation. Interestingly, SPARC-driven gene expression signatures obtained from these murine models predicted the clinical outcome of patients with HER2-enriched breast cancer subtypes. In total, the results reveal that SPARC and its downstream effectors are attractive targets for antimetastatic therapies in breast cancer. These findings shed light on the prometastatic role of SPARC, a key protein expressed by breast cancer cells and surrounding stroma, with important consequences for disease outcome. .

Prenatal and postnatal zinc deficiency induces alterations in cardiac apoptotic, inflammatory, oxidative, and nitric oxide pathways that could predispose the onset of cardiovascular diseases in adult life.

Patients with ovarian cancer present peritoneal ascites at recurrence as a marker of disseminated disease and dismal prognosis. Oncolytic immunotherapy is an emerging approach for the treatment of disseminated cancer. In the present work, we constructed a novel oncolytic adenovirus, AR2011, to target malignant ovarian tumors. AR2011 exhibited a clear lytic effect in vitro in human ovarian cancer cell lines and malignant cells obtained from ascitic fluids (AFs) of patients with ovarian cancer. AR2011 activity was neutralized by antibodies present in 31 samples of patient-derived AFs. However, this blockade was overridden by preloading menstrual blood stem cells (MenSCs) with AR2011 (MenSC-AR), since AFs exerted no in vitro inhibitory effect on viral lytic activity under these conditions. Moreover, soluble factors present in AFs act as MenSC chemoattractants. MenSC-AR treatment of nude mice carrying established peritoneal carcinomatosis following administration of human ovarian cancer cells was able to inhibit tumor growth at levels similar to those observed with AR2011 alone. This study demonstrates that MenSCs can be used to override the blockade that AFs exert on viral oncolytic effects.

<p>Figure S1. Association between SPARC expression and distant metastasis free survival (RFS) in breast cancer patients with different PAM50 subtypes. Figure S2. Downregulation of SPARC expression in 4T1 and LM3 murine breast cancer cell lines. Figure S3. SPARC targeting inhibits primary tumor growth and lung metastasis establishment. Figure S4. SPARC-deficient cells exhibit a delay in cell cycle progression. Figure S5. Transcriptomic analysis of SPARC-deficient tumors revealed changes in cell-ECM interaction and immune response. Figure S6. Enforced expression of COX-2 in SPARC-deficient 4T1 cells partially restores cells capacity to grow as primary tumor. Figure S7. SPARC targeting impairs invasive capacity of breast cancer cells. Figure S8. Association between hS-PT and hS-ESM expression and distant metastasis free survival (RFS) in breast cancer patients with different PAM50 subtypes.</p>

<p>Figure S1. Association between SPARC expression and distant metastasis free survival (RFS) in breast cancer patients with different PAM50 subtypes. Figure S2. Downregulation of SPARC expression in 4T1 and LM3 murine breast cancer cell lines. Figure S3. SPARC targeting inhibits primary tumor growth and lung metastasis establishment. Figure S4. SPARC-deficient cells exhibit a delay in cell cycle progression. Figure S5. Transcriptomic analysis of SPARC-deficient tumors revealed changes in cell-ECM interaction and immune response. Figure S6. Enforced expression of COX-2 in SPARC-deficient 4T1 cells partially restores cells capacity to grow as primary tumor. Figure S7. SPARC targeting impairs invasive capacity of breast cancer cells. Figure S8. Association between hS-PT and hS-ESM expression and distant metastasis free survival (RFS) in breast cancer patients with different PAM50 subtypes.</p>

<p>This file contains legends of Supplementary Figures S1-S8</p>