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Cambridge Institute for Medical Research |
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| School of Clinical Medicine > CIMR > Principal Investigators > Prof David Lomas > Stefan Marciniak |
Dr Stefan J. Marciniak |
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ER stress and human disease Endoplasmic reticulum (ER) dysfunction plays a central role in many human diseases, including diabetes and cancer. It is therefore crucial to understand the biological processes it provokes. When incorrectly folded ER proteins accumulate, the cell is said to experience "ER stress". In order that this does not occur, homeostatic pathways exist that defend the balance between ER client protein synthetic rate and the organelle's folding capacity. These pathways are collectively called the unfolded protein response (UPR). Early on, during ER stress protein synthesis is attenuated due to the phosphorylation of eIF2a by PERK, an ER-resident kinase. It is now clear that prolonged activation of the UPR can also lead to cell death and we have shown that some of this toxicity is a consequence of translational recovery, brought about by the PP1 regulatory subunit, GADD34. In order to identify novel factors involved in cellular survival during ER stress, we are currently studying the pathways that regulate both PERK and GADD34. To this end, we are using biochemical, cell culture and Drosophila models of ER stress signalling. Our long-term goal is to use these discoveries to develop novel therapies for the many human diseases in which ER is involved. Funding
Collaborators
Recent publications Kroeger H., Miranda E., Macleod I., Pérez J., Crowther D.C., Marciniak S.J.*, Lomas D.A.* (2009) Endoplasmic Reticulum-associated Degradation (ERAD) and Autophagy Cooperate to Degrade Polymerogenic Mutant Serpins. J Biol Chem. 284: 22793-802. Ekeowa U.I., Gooptu B., Belorgey D., Hägglöf P., Karlsson-Li S., Miranda E., Pérez J., MacLeod I., Kroger H., Marciniak S.J., Crowther D.C., Lomas D.A. (2009) alpha1-Antitrypsin deficiency, chronic obstructive pulmonary disease and the serpinopathies. Clin Sci (Lond). 116:837-50. Davies M.J., Miranda E., Roussel B.D., Kaufman R.J., Marciniak S.J.*, Lomas D.A.* (2009) Neuroserpin Polymers Activate NF-{kappa}B by a Calcium Signaling Pathway That Is Independent of the Unfolded Protein Response. J Biol Chem. 284: 18202-9. Marciniak S.J. & Lomas D.A. (2009) What can naturally occurring mutations tell us about the pathogenesis of COPD? Thorax 64: 359-64. Marciniak S.J. & Lomas D.A. (2008). Serpins, intracellular firewalls and necrosis. Trends Cell Biol. 18:45-47. Marciniak S.J. & Ron D. (2006). Endoplasmic reticulum stress signalling in disease. Physiol Rev. 86: 1133-49. Marciniak S.J., Garcia-Bonilla L., Hu J., Harding H.P., Ron D. (2006). Activation-dependent substrate recruitment by the eukaryotic translation initiation factor 2 kinase PERK. J Cell Biol. 172: 201-9. Pereira R.C., Stadmeyer L., Marciniak S.J., Ron D., Canalis E. (2006). C/EBP homologous protein is necessary for normal osteoblastic function. J Cell Biochem. 97:633-640. Harding HP, Zhang Y, Khersonsky S, Marciniak S, Scheuner D, Kaufman RJ, Javitt N, Chang YT, Ron D. (2005). Bioactive small molecules reveal antagonism between the integrated stress response and sterol-regulated gene expression. Cell Metab. 2:361-71. Silva R.M., Ries V., Oo T.F., Yarygina O., Jackson-Lewis V., Ryu E.J., Lu P.D., Marciniak S.J., Ron D., Przedborski S., Kholodilov N., Greene L.A., Burke R.E. (2005). CHOP/GADD153 is a mediator of apoptotic death in substantia nigra dopamine neurons in an in vivo neurotoxin model of parkinsonism. J Neurochem. 95:974-8. Marciniak S.J, Yun CY, Oyadomari S, Novoa I, Zhang Y, Jungreis R, Nagata K, Harding HP, Ron D. (2004). CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev. 2004 18:3066-77. Lu P.D., Jousse C., Marciniak S.J., Zhang Y., Novoa I., Scheuner D., Kaufman R.J., Ron D., Harding H.P. (2004). Cytoprotection by pre-emptive conditional phosphorylation of translation initiation factor 2. EMBO J. 23:169-79.
Contact information Dr Stefan J. Marciniak Title: MRC Clinician Scientist & Honorary Consultant Physician |
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