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Tag Archives: hypoxia

Friday Science Review: December 18, 2009

Advancing Cell Research with Proteomic Tools: Advances in technology – particularly in proteomics – are allowing scientists to perform research in more complex systems, a complexity that more closely reflects the situation inside the body.  In the latest trend, researchers can label two different populations of cells with different modified amino acids and use mass spectrometry to distinguish proteins derived from one population versus the other.  This strategy was recently applied to study the EphB2 receptor protein, which plays an important role in a cell’s communication with an adjacent cell expressing ephrin-B1 protein.  Differential labeling allowed the researchers to determine the unique (and similar) molecular signaling network in each cell population as they coordinate their self-organizational activity.  It’s a powerful tool that can be adapted to investigate various systems that cannot be studied in isolation.  The research was performed in Dr. Anthony Pawson’s group at the Samuel Lunenfeld Research Institute and is published in the journal Science.

New Member in the Protein Synthesis Club: After decades of studying and trying to fully understand the mRNA translational machinery for protein synthesis, new components in this complex process continue to be discovered.  The latest is a protein called DHX29, a helicase enzyme that helps to untangle the nucleic acid during the initiation phase of translation.  Down-regulating the enzyme holds up protein synthesis and presents a possible target point to block cancer cells from growing.  Indeed, when the researchers blocked DHX29 in cancer cells, tumour growth was significantly reduced.  Dr. Nahum Sonenberg was the lead author of the study reported in the early online edition of the Proceedings of the National Academy of Sciences.

PS.  Congratulations to Dr. Sonenberg in becoming the 2009 Researcher of the Year for Biomedical and Clinical Research presented by CIHR.

Low Oxygen Response in Cancer Cells:  Within a large tumour, there may be areas of hypoxic microenvironments – regions that are under low oxygen conditions.  Cells in this environment undergo a stress response to try to adapt by carrying out a process called autophagy.  The consequence of this is that the cancer cells ‘get tough’ and subsequently become resistant to radiation therapy.  This recent study investigated one of the possible cell adaptation methods through activation of the unfolded protein response (UPR) pathway.  Induction of two key proteins, MAP1LC3B and PERK, were required for autophagy.  They also demonstrated that inhibition of autophagy resulted in the cells becoming sensitive to hypoxia and irradiation.  Thus, the molecular players involved in autophagy may be good therapeutic targets.  Dr. Bradly Wouters at the Ontario Cancer Institute led the research and reports the findings in the Journal of Clinical Investigation.

Teasing out the Role of E2f Transcription Factors: Members of the E2f family of transcription factors are key regulators that commit cells through the cell division process.  Information in the literature is somewhat perplexing regarding whether they are essential for this process and different studies will support one argument or the other.  New research settles this debate – at least for the E2f1-3 isoform.  Through a series of expression and deletion studies and looking at the different molecular players involved, it was concluded that E2fs are not absolutely required for normal cell division.  The surprise finding is that E2f1-3 is necessary for cell survival in development and its function switches from ‘activator’ in progenitor cells to ‘repressor’ mode in differentiating cells.  The research was conducted at Toronto Western Research Institute by Dr. Rod Bremner’s team and appears in this week’s Nature journal.  The story is corroborated in another similar study in the same issue.

Possible Risk for Diabetes or Heart Disease: A large genome-wide study revealed an association between a polymorphism in the ARL15 gene (ADP-ribosylation factor-like 15) with lower levels adiponectin.  Adiponectin is a fat cell protein and its circulating level is inversely associated with type 2 diabetes and coronary heart disease.  Accordingly, the polymorphism is also associated to some degree with higher risk of heart disease, diabetes and other metabolic related traits.  Surely this requires a more in depth molecular study but this is a good example of how you can sift through large amounts of data from various genome-wide studies and fish out an important finding.  Dr. Brent Richards, now at McGill University, is the corresponding author of the study published in PLoS Genetics.

Genetic Mutation in Intellectual Disability: Approximately 50% of intellectual disability cases are not related to other syndromes.  In these cases, an explanation for the intellectual disability may lie in the gene called TRAPPC9, where a mutation in the gene causes a truncated form of the protein and renders it inactive.  The research team led by Dr. John Vincent at the Centre for Addiction and Mental Health used microarrays to screen a family that had seven members with non-syndromic intellectual disability to map the TRAPPC9 gene.  Additional families with mutations affecting the same gene validated the importance of TRAPPC9, which encodes proteins involved in the NF-κB signaling pathway.  With this new knowledge, researchers can screen patients or family members to track the mutation and also dig deeper into the mechanisms in the brain that affects cognitive development.  The study appears in the American Journal of Human Genetics.

Friday Science Review: December 4, 2009

Universal Cancer Signalling Pathway: This is an interesting new twist on cancer signalling that may make scientists rethink how to tackle the disease.  It is thought that there is no single cure for cancer as the hetergenous disease may arise from mutations in a number of different pathways.  In this report, however, researchers demonstrate that many of the cancers converge on HIF-2a, part of the oxygen-sensing system that is required for tumours to grow.  By inhibiting HIF-2a, they could attenuate the growth of a diverse number of aggressive cancers including glioblastomas, colorectal tumours, and non-small cell lung carcinomas.  This universal cancer axis converging on HIF-2a could turn out to be a silver-bullet for cancer therapy.   Dr. Stephen Lee at the University of Ottawa led the team and describes the research in the online edition of the Proceedings of the National Academy of Sciences.

SKP’ing Stem Cells: A special type of cell called SKPs (skin-derived precursors) may be the elusive adult dermal stem cell involved in regenerating skin, wound-healing, and keeping hair healthy and growing.  In the study, researchers characterized the specialized population of cells and determined that SKPs can self-renew, maintain their ability to transform into other cells types, and regenerate hair follicles or other dermal cell types when grafted.  These properties are suggestive that SKPs are indeed THE dermal stem cells and may have important future applications such as in hair restoration and wound-healing.  Dr. Jeffrey Biernaskie completed the research in the lab of Dr. Freda Miller at Sickkids Hospital and recently started his own group at the University of Calgary.  The report appears in this latest edition of Cell Stem Cell.

Comparative Genomics Links Autism and Schizophrenia: A new study comparing the genomes of autistic patients and schizophrenic patients proved the connection between the two disorders that were previously thought to share behavioural similarities.  Both illnesses are associated with anomalies in the same region of the genome but differ substantially in the nature of the genetic changes.  Part of the genomic region is missing in autistic patients whereas extra copies of the genome are present in schizophrenic patients.  The affected genes appear to control head size and brain growth with overdevelopment of the brain in autistic patients and underdevelopment in schizophrenics.  By knowing that the two disorders are genetically linked, research on one disorder immediately provides clues for the other and will aid in advancing treatment options for both.  The study was conducted by Dr. Bernard Crespi’s group at Simon Fraser University and is reported in the Proceedings of the National Academy of Sciences.

Signalling Links in Neurological Disorders: Perturbations in either Dopamine or BDNF (brain-derived nerutrophic factor) pathways are implicated in neurological disorders.  Researchers have now defined the molecular relationship linking the two pathways to similar disorders.  The calcium signalling cascade is the key intermediate between dopamine receptor activation and BDNF production leading to neuronal growth.  With this new understanding of the pathways associated with schizophrenia, depression, and drug addiction, additional molecular targets are available for potential therapeutic intervention.  The study was led by Dr. Susan George at the Centre for Addiction and Mental Health (Toronto) and is reported in the early online edition of the Proceedings of the National Academy of Sciences.

Small Molecule Pathway Database: SMPDB (www.smpdb.ca) is an interactive, visual database containing more than 350 small-molecule pathways found in humans.  It is designed to support drug discovery research and pathway elucidation by employing clinical metabolomics, transcriptomics, proteomics and systems biology information.  The pathways describe relevant organs, organelles, subcellular compartments, protein cofactors, protein locations, metabolite locations, chemical structures and protein quaternary structures.  SMPBP is a very useful tool that was put together by Dr. David Wishart’s group at the University of Alberta and is described in detail in Nucleic Acids Research.

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