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Im Y.K.,Lady Davis Institute for Medical Research | La Selva R.,Lady Davis Institute for Medical Research | Gandin V.,Lady Davis Institute for Medical Research | Ha J.R.,Lady Davis Institute for Medical Research | And 5 more authors.
Oncogene | Year: 2014

The ShcA adaptor protein is engaged by numerous receptor tyrosine kinases (RTKs) in breast cancer cells. Once activated, RTKs phosphorylate three key tyrosine phosphorylation sites (Y239, Y240 and Y317) within ShcA that creates a docking site for Grb2/SOS and Grb2/Gab-containing complexes to activate the MAPK and AKT signaling pathways, respectively. We previously demonstrated that a tyrosine to phenylalanine substitution of the ShcA tyrosine phosphorylation sites (Shc3F-Y239/240/313F) significantly impairs breast tumor growth and angiogenesis in transgenic mouse models, in part, through the regulation of vascular endothelial growth factor (VEGF) production. Despite this fact, the underlying molecular mechanisms by which ShcA transduces pro-tumorigenic signals in breast cancer cells remain poorly defined. In this study, we demonstrate that ShcA-dependent activation of AKT, but not the RAS/MAPK pathway, induces VEGF production by bolstering VEGF mRNA translation. Accordingly, ShcA drives breast tumor growth and angiogenesis in vivo in a 4E-BP-dependent manner. These findings establish ShcA as a biological bridge that links AKT activation downstream of RTKs to cap-dependent VEGF mRNA translation in order to promote mammary tumorigenesis.Oncogene advance online publication, 19 May 2014; doi:10.1038/onc.2014.110.

Stewart K.,McGill University | Stewart K.,Goodman Cancer Research Center | Bouchard M.,McGill University | Bouchard M.,Goodman Cancer Research Center
Pediatric Nephrology | Year: 2011

Development of the mammalian urogenital system requires a balance between survival and programmed cell death. Pro-survival molecules are crucial in preserving metanephric mesenchyme viability, and thus allowing nephrogenesis to proceed. At the same time, localized areas of apoptosis mediated by effector caspases are required for the appropriate morphogenesis of the kidney and urinary tract. Activation of the intrinsic pathway of apoptosis seems to be fundamental to the progression of cell death necessary to aid ureteric bud branching, nephrogenesis, and ureter-bladder connection. Here, we review what is currently known about survival and apoptosis in building functional kidneys and urinary tracts. © 2011 IPNA.

Feldhammer M.,Goodman Cancer Research Center | Feldhammer M.,McGill University | Uetani N.,Goodman Cancer Research Center | Miranda-Saavedra D.,Osaka University | And 2 more authors.
Critical Reviews in Biochemistry and Molecular Biology | Year: 2013

Our understanding of the fundamental regulatory roles that tyrosine phosphatases play within cells has advanced significantly in the last two decades. Out-dated ideas that tyrosine phosphatases acts solely as the "off" switch counterbalancing the action of tyrosine kinases has proved to be flawed. PTP1B is the most characterized of all the tyrosine phosphatases and it acts as a critical negative and positive regulator of numerous signaling cascades. PTP1B's direct regulation of the insulin and the leptin receptors makes it an ideal therapeutic target for type II diabetes and obesity. Moreover, the last decade has also seen several reports establishing PTP1B as key player in cancer serving as both tumor suppressor and tumor promoter depending on the cellular context. Despite many key advances in these fields one largely ignored area is what role PTP1B may play in the modulation of immune signaling. The important recognition that PTP1B is a major negative regulator of Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling throughout evolution places it as a key link between metabolic diseases and inflammation, as well as a unique regulator between immune response and cancer. This review looks at the emergence of PTP1B through evolution, and then explore at the cell and systemic levels how it is controlled physiologically. The second half of the review will focus on the role(s) PTP1B can play in disease and in particular its involvement in metabolic syndromes and cancer. Finally we will briefly examine several novel directions in the development of PTP1B pharmacological inhibitors. © 2013 Informa Healthcare USA, Inc. All rights reserved: reproduction in whole or part not permitted. © 2013 Informa Healthcare USA.

Bhat M.,McGill University | Skill N.,Indiana University | Marcus V.,McGill University | Deschenes M.,McGill University | And 14 more authors.
BMC Gastroenterology | Year: 2015

Background: The management of hepatocellular carcinoma (HCC) is limited by the lack of adequate screening biomarkers and chemotherapy. In response, there has been much interest in tumor metabolism as a therapeutic target. PCSK9 stimulates internalization of the LDL-receptor, decreases cholesterol uptake into hepatocytes and affects liver regeneration. Thus, we investigated whether PCSK9 expression is altered in HCC, influencing its ability to harness cholesterol metabolism. Methods: Thirty-nine patients undergoing partial hepatectomy or liver transplantation for HCC were consented for use of HCC tissue to construct a tissue microarray (TMA). The TMA was immunostained for PCSK9. Imagescope software was used to objectively determine staining, and assess for pathological and clinical correlations. PCSK9 and LDL receptor mRNA levels in flash-frozen HCC and adjacent liver tissue were determined by quantitative RT-PCR. Serum PCSK9 levels were determined by ELISA. Results: By immunohistochemistry, there was significantly lower expression of PCSK9 in HCC as compared to adjacent cirrhosis (p-value < 0.0001, wilcoxon signed-rank test). Significantly greater staining of PCSK9 was present in cirrhosis compared to HCC (p value <0.0001), and positivity (percentage of positive cells) was significantly greater in cirrhosis compared to HCC (p-value < 0.0001). Conversely, significantly higher expression of LDL-R was present in HCC as compared to the adjacent cirrhosis (p-value < 0.0001). There was no significant correlation of PCSK9 staining with grade of tumor, but there were significant correlations between PCSK9 staining and stage of fibrosis, according to spearman correlation test. PCSK9 mRNA levels were relatively less abundant within HCC compared to adjacent liver tissue (p-value =0.08) and normal control tissue (p-value =0.02). In contrast, serum PCSK9 levels were significantly increased among patients with HCC compared to those with chronic liver disease without HCC (p-value =0.029). LDL receptor mRNA was consistantly greater in HCC when compared to normal control tissue (p-value = 0.06) and, in general, was significantly greater in HCC when compared to adjacent liver (p-value = 0.04). Conclusions: The decreased expression of PCSK9 and conversely increased LDL-R expression in HCC suggests that HCC modulates its local microenvironment to enable a constant energy supply. Larger-scale studies should be conducted to determine whether PCSK9 could be a therapeutic target for HCC. © 2015 Bhat et al.

Bhat M.,Goodman Cancer Research Center | Bhat M.,McGill University | Robichaud N.,Goodman Cancer Research Center | Robichaud N.,McGill University | And 8 more authors.
Nature Reviews Drug Discovery | Year: 2015

Dysregulation of mRNA translation is a frequent feature of neoplasia. Many oncogenes and tumour suppressors affect the translation machinery, making aberrant translation a widespread characteristic of tumour cells, independent of the genetic make-up of the cancer. Therefore, therapeutic agents that target components of the protein synthesis apparatus hold promise as novel anticancer drugs that can overcome intra-tumour heterogeneity. In this Review, we discuss the role of translation in cancer, with a particular focus on the eIF4F (eukaryotic translation initiation factor 4F) complex, and provide an overview of recent efforts aiming to 'translate' these results to the clinic. © 2015 Macmillan Publishers Limited.

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