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CHMI 4237 E Special topics in Biochemistry

CHMI 4237 E Special topics in Biochemistry. Stress signaling. Eric R. Gauthier, Ph.D . Dept . Chemistry - Biochemistry Laurentian University. Hypoxia. Mechanical. Oxidative. Viruses. Chemicals. Nutrient. Radiation. Osmotic pressure. Cell stresses. Heat. ?. Cell cycle arrest.

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CHMI 4237 E Special topics in Biochemistry

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  1. CHMI 4237 ESpecialtopics in Biochemistry Stress signaling Eric R. Gauthier, Ph.D. Dept. Chemistry-Biochemistry LaurentianUniversity CHMI 4237 E - Winter 2010

  2. Hypoxia Mechanical Oxidative Viruses Chemicals Nutrient Radiation Osmotic pressure Cell stresses Heat CHMI 4237 E - Winter 2010

  3. ? Cell cycle arrest Adaptation Death Cellular responses to stress CHMI 4237 E - Winter 2010

  4. ? - Metabolic rewiring - Differentiation Cell cycle arrest Adaptation - Plasticity - Motility Death - Defense Cellular responses to stress - Aging CHMI 4237 E - Winter 2010

  5. Cellular responses to stress CHMI 4237 E - Winter 2010

  6. Food shortage Cell cycle Protein synthesis Alternative food source OR Commit suicide 1. Response to nutrientstarvation CHMI 4237 E - Winter 2010

  7. http://8e.devbio.com/image.php?id=187 1. Response to nutrientstarvation Blocking ATP-vorousprocesses CHMI 4237 E - Winter 2010

  8. http://8e.devbio.com/image.php?id=188 CHMI 4237 E - Winter 2010

  9. http://8e.devbio.com/image.php?id=188 CHMI 4237 E - Winter 2010

  10. eIF2 phosphorylation leads to translation arrest http://deverlab.nichd.nih.gov/graphics/fig3a.gif CHMI 4237 E - Winter 2010

  11. GCN2 – linkingaminoacidavailabilitywith translation http://deverlab.nichd.nih.gov/sub_rec.htm CHMI 4237 E - Winter 2010 The EMBO Journal Vol. 20 No. 6 pp. 1425-1438, 2001

  12. Trends in Endocrinology & MetabolismVolume 20, Issue 9, November 2009, Pages 436-443 uORF = - upstream open reading frame (i.e. upstream of the ATF4 ORF) - uORF1 encodes for a 3-amino acid protein - uORF2 overlaps with the ATF4 ORF but is out of frame. ATF4 translation is INCREASED when eIF2 isphosphorylated… CHMI 4237 E - Winter 2010

  13. ATF4 translation islimitedwhenaminoacids are plentyful Trends in Endocrinology & MetabolismVolume 20, Issue 9, November 2009, Pages 436-443 CHMI 4237 E - Winter 2010

  14. ATF4 translation islimitedwhenaminoacids are plentyful Trends in Endocrinology & MetabolismVolume 20, Issue 9, November 2009, Pages 436-443 CHMI 4237 E - Winter 2010

  15. Trends in Endocrinology & MetabolismVolume 20, Issue 9, November 2009, Pages 436-443 Transcription Initiation machinery ATF4 genetargets CHMI 4237 E - Winter 2010

  16. Trends in Endocrinology & MetabolismVolume 20, Issue 9, November 2009, Pages 436-443 ATF4 genetargets CHMI 4237 E - Winter 2010

  17. Molecular Cell, Vol. 18, 141–148, April 15, 2005 GCN2/eIF2 and feedingbehavior CHMI 4237 E - Winter 2010

  18. mTOR: • Protein serine kinase • Same family as ATM • Inhibited by Rapamycin • Rapamycin: secreted by Streptomyces hygroscopicus • From Rapa Nui (aka Easter Island) • Senses: • Glucose • Amino acids • Energy levels • Triggers: • AKT activation • Translation • Proliferation NATURE REvIEWS | Molecular cell Biology vOlUME 10 | MAy 2009 | 307 mTOR: the art of sensingnutrients • HEAT repeats: protein interaction domain • FAT domain: domain structure shared by FRAP, ATM and TRRAP CHMI 4237 E - Winter 2010

  19. mTORC1: targeting translation CHMI 4237 E - Winter 2010 Oncogene (2006) 25, 6416–6422

  20. mTORC1 p70 S6K S6 ribosomal protein eIF4B mTORC1: targeting translation ↑ eIF4A helicase activity NATURE REvIEWS | Molecular cell Biology vOlUME 10 | MAy 2009 | 307 ↑ translation efficiency CHMI 4237 E - Winter 2010

  21. mTORC1: widerangingeffects http://www.cellsignal.com/reference/pathway/mTor.html CHMI 4237 E - Winter 2010

  22. TSC 1/2: • GTPase activating enzyme  targets Rheb • Mutated in patients with Tuberous Sclerosis • Rheb: • small G protein • In GTP-bound form: activates mTOR • PRAS40 • Binds mTORC and inhibits it; • Dissociates form mTORC upon phosphorylation by AKT AKT PRAS40 mTOR GbL Raptor PO4 mTORC1 regulation PRAS40 mTOR CHMI 4237 E - Winter 2010 GbL Raptor NATURE REVIEWS | DRUG DISCOVERY VOLUME 4 | DECEMBER 2005 | 989

  23. NATURE REvIEWS | Molecular cell Biology vOlUME 10 | MAy 2009 | 307 mTORC1 regulation CHMI 4237 E - Winter 2010 http://www.lsi.umich.edu/files/ken_research_fig1.jpg

  24. NATURE REvIEWS | Molecular cell Biology vOlUME 10 | MAy 2009 | 307 Glucose and mTORC1 CHMI 4237 E - Winter 2010 http://www.lsi.umich.edu/files/ken_research_fig1.jpg

  25. GLUCOSE Cellular processes Glycogen Glycolysis ATP ADP ATP Energy reserves Acetyl-CoA Fatty acids ETC Citrate NADH TCA ETC When glucose in plenty… CO2 ATP ATP CHMI 4237 E - Winter 2010

  26. GLUCOSE Glycogen Glycolysis ATP Energy reserves Acetyl-CoA Fatty acids Citrate NADH TCA Glutamine ETC When glucose in scarce… CO2 ATP ATP CHMI 4237 E - Winter 2010

  27. ADP Kinase AMP ADP ADP ATP But, how are glucose levelssensed? CHMI 4237 E - Winter 2010

  28. ADP Kinase AMP ADP ADP ATP AMPK Adaptation But, how are glucose levelssensed? CHMI 4237 E - Winter 2010

  29. AMPK and mTORC1 http://www.cellbiol.net/ste/alpobesity4.php CHMI 4237 E - Winter 2010

  30. http://www.cellsignal.com/reference/pathway/AMPK.html Othertargets of AMPK CHMI 4237 E - Winter 2010

  31. Othertargets of AMPK- carbohydratemetabolism CHMI 4237 E - Winter 2010

  32. Othertargets of AMPK- lipidmetabolism CHMI 4237 E - Winter 2010

  33. Othertargets of AMPK- cell cycle CHMI 4237 E - Winter 2010

  34. Other triggers of AMPK CHMI 4237 E - Winter 2010

  35. Adrenalin Other triggers of AMPK- adrenalin http://www.cellbiol.net/ste/alpobesity4.php CHMI 4237 E - Winter 2010

  36. Other triggers of AMPK- adrenalin http://www.cellbiol.net/ste/alpobesity4.php CHMI 4237 E - Winter 2010

  37. Other triggers of AMPK- adrenalin http://www.cellbiol.net/ste/alpobesity4.php CHMI 4237 E - Winter 2010

  38. http://stke.sciencemag.org/content/sigtrans/vol2006/issue346/images/large/3462006re7F1.jpeghttp://stke.sciencemag.org/content/sigtrans/vol2006/issue346/images/large/3462006re7F1.jpeg Other triggers of AMPK- Insulin CHMI 4237 E - Winter 2010

  39. Aminoacids and mTOR CHMI 4237 E - Winter 2010 http://www.efdeportes.com/efd131/leucine-stimulates-mtor-01.jpg

  40. Aminoacids and mTOR http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2677387/pdf/nihms103321.pdf CHMI 4237 E - Winter 2010

  41. Autophagy – cellcannibalism 5 NOVEMBER 2004 VOL 306 SCIENCE nature cell biology volume 9 | number 10 | O CTOBER 2007 CHMI 4237 E - Winter 2010

  42. Autophagy – cellcannibalism CHMI 4237 E - Winter 2010 Biochem. J. (2005) 391, 191–202

  43. Phagophore Nucleation Phagophore Elongation Autophagosome 9 PI3P Atg23/27 Vps34 2 Membrane transport? Atg2/18 Vps34 1 13 18 Atg9 LC3-II mTOR Atg3 Atg16 PtdE 1 Atg10 Atg7 LC3-II Gly Starvation Atg1/ ULK1 13 Atg4 Atg13 LC3-I Atg5 Atg12 Autophagy: autophagosome formation

  44. http://www.cellsignal.com/products/4108.html LC3 – a marker of autophagy CHMI 4237 E - Winter 2010

  45. Autophagosome Amino acids Atg22 Cathepsins Autophagy: fusion with lysosome H+ ATP Autolysosome H+ ADP + Pi Lysosome

  46. Increasing autophagy Chloroquine Vps34 PI3P Beclin UVRAC 9 p150 p150 H+ Lipid transport? ATP H+ 1 13 ADP + Pi Lysosome Atg9 Vps34 mTOR 3-MA 1 13 Rapamycin Beclin Bcl2 UVRAC Bcl2 Bafilomycin A Inhibiting autophagy Autophagy - modulation

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