Human GTSE-1 regulates p21(CIP1/WAF1) stability conferring resistance to paclitaxel treatment

p21CIP1/WAF1 belongs to the CIP/KIP family of Cdk inhibitors, and its expression is tightly controlled during the cell cycle, mainly by transcriptional and post-translational mechanisms. Fine regulation of p21CIP1/WAF1 levels is critical for cell cycle control and for cellular response to stress. In the present work, we describe a novel mechanism to modulate p21CIP1/WAF1 levels mediated by the human GTSE-1 (G2 and S phase-expressed-1) protein. Our results provide evidence that hGTSE-1 protects p21CIP1/WAF1 from proteasome-dependent degradation as part of a functional complex containing the Hsp90-bindingTPRprotein WISp39. We further show that the hGTSE-1 N-terminal portion is sufficient for p21CIP1/WAF1 binding and stabilization. Finally, we demonstrate that hGTSE-1 mediated-p21CIP1/WAF1 stabilization is clearly involved in the ability of cells to counteract cytotoxicity induced by the microtubule poison paclitaxel

GTSE1 Is a Microtubule Plus-End Tracking Protein That Regulates EB1-Dependent Cell Migration

The regulation of cell migration is a highly complex process that is often compromised when cancer cells become metastatic. The microtubule cytoskeleton is necessary for cell migration, but how microtubules and microtubule-associated proteins regulate multiple pathways promoting cell migration remains unclear. Microtubule plus-end binding proteins (+TIPs) are emerging as important players in many cellular functions, including cell migration. Here we identify a +TIP, GTSE1, that promotes cell migration. GTSE1 accumulates at growing microtubule plus ends through interaction with the EB1+TIP. The EB1-dependent +TIP activity of GTSE1 is required for cell migration, as well as for microtubule-dependent disassembly of focal adhesions. GTSE1 protein levels determine the migratory capacity of both nontransformed and breast cancer cell lines. In breast cancers, increased GTSE1 expression correlates with invasive potential, tumor stage, and time to distant metastasis, suggesting that misregulation of GTSE1 expression could be associated with increased invasive potential. © 2012 Scolz et al.Fil:Monte, M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina

Potential pathophysiological role of microRNA 193b-5p in human placentae from pregnancies complicated by preeclampsia and intrauterine growth restriction.

Preeclampsia (PE) and intrauterine growth restriction (IUGR) are pregnancy complications resulting from abnormal placental development. MicroRNAs can regulate placental development and contribute to disease, by influencing gene expression. Our previous study revealed an increase in miR-193b-5p expression in placentae from patients with early-onset pregnancy complications and identified candidate gene targets for miR-193b-5p. The purpose of this study is two-fold, first to validate candidate gene targets predicted for miR-193b-5p from microRNA-RNA expression data. Second, to overexpress miR-193b-5p in a trophoblast cell line (HTR-8/SVneo) to assess impact on trophoblast cell proliferation and migration. Integration of the miRNA and RNA sequencing expression data revealed 10 candidate gene targets for miR-193b-5p across all patient groups (PE only, IUGR only, PE + IUGR). Luciferase experiments identified two gene targets for miR-193b-5p, APLN and FGF13. Real-time PCR confirmed a median 45% decrease of FGF13 expression across 3 patient groups, and 50% decrease of APLN expression in patients with PE + IUGR. Following transfection of HTR-8/SVneo cells with miR-193b-5p mimics, APLN and FGF13 mRNA expression in HTR-8/SVneo was reduced by a median percentage of 30% and 45%, respectively. Concomitantly, HTR-8/SVneo cells demonstrate 40% reduction in cell migration. APLN and FGF13 immunoreactivity was identified strongly in the cytotrophoblast cells of the human placentae. These findings suggest that miR-193b-5p may contribute to trophoblast dysfunction observed in pregnancy complications such as PE and IUGR

Stem Cell Therapy for Pediatric Dilated Cardiomyopathy

Dilated cardiomyopathy is a serious and life-threatening disorder in children. It is the most common form of pediatric cardiomyopathy. Therapy for this condition has varied little over the last several decades and mortality continues to be high. Currently, children with dilated cardiomyopathy are treated with pharmacological agents and mechanical support, but most require heart transplantation and survival rates are not optimal. The lack of common treatment guidelines and inadequate survival rates after transplantation necessitates more therapeutic clinical trials. Stem cell and cell-based therapies offer an innovative approach to restore cardiac structure and function towards normal, possibly reducing the need for aggressive therapies and cardiac transplantation. Mesenchymal stem cells and cardiac stem cells may be the most promising cell types for treating children with dilated cardiomyopathy. The medical community must begin a systematic investigation of the benefits of current and novel treatments such as stem cell therapies for treating pediatric dilated cardiomyopathy

FKBP (FK506 Binding Protein)

In the 70s, after a decade from the purification of cyclosporine, a selective immunosuppressant agent and potent tool in transplantation medicine, a novel molecule was purified from bacteria Streptomyces tsukubaensis. This molecule, called FK506, showed the same selective immunosuppressant action as cyclosporine but was 10 to 100 fold more potent. In an attempt to clarify the molecular mechanism through which the new drug exerted such a selective effect on T-cells activation, two laboratories identified the cytosolic receptor for FK506. This so-called FK506 binding protein (FKBP) was purified from bovine thymus, human spleen, and Jurkat T-cell line. The isolated FKBP had an approximate molecular mass of 14 kDa and showed an isomerase activity similar to the recently purified cyclosporine-binding protein, cyclophilin, but, it was inhibited by FK506 and rapamycin but not cyclosporine. The subsequent cloning of FKBP gene revealed that FKBP and cyclophilin had dissimilar sequences in spite of their common enzymatic activity. The identified FKBP gene encoded for a protein of 108 aminoacids with a relative molecular mass of 11,819. For this reason, the progenitor of this nascent class of proteins was later known as FKBP12. The subsequent studies showed that FKBP12 was just a member of a ubiquitous and evolutionarily conserved sub-family of proteins which differ from each other in their molecular weight and structure. All FKBPs share a highly conserved domain, termed “FK-12 like domain”, capable of binding to FK506 and exerting isomerase properties, i.e. interconversion from cis-to-trans and trans-to-cis of peptide bonds involving proline, on protein substrates. A schematic historical background of the 17 FKBPs so far identified is shown. A general overview of FKBP structure, function and eventually associated disease is given in this monograph, with the order of proteins following the chronology of discovery