Endoplasmic reticulum stress in disease

Proteins destined for secretion or for insertion into the cell membrane are first folded within the endoplasmic reticulum.  The process of protein folding can become defective in many disease states such as hypoxia, malignancy and some forms of diabetes.  When the level of misfolded proteins within the endoplasmic reticulum increases, the cell is said to experience “endoplasmic reticulum stress”.

We wish to understand the cellular consequences of endoplasmic reticulum stress; in particular its effects on tissue growth and cell survival.  In doing so, we hope to identify targets for the development of novel therapies.

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Selected References

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2015 Papers

Actin dynamics tune the integrated stress response by regulating eukaryotic initiation factor 2α dephosphorylation. Chambers JE, Dalton LE, Clarke HJ, Malzer E, Dominicus CS, Patel V, Moorhead G, Ron D, Marciniak SJ. Elife. 2015 Mar 16;4. doi: 10.7554/eLife.04872. [Epub ahead of print]
G-actin provides substrate-specificity to eukaryotic initiation factor 2α holophosphatases.
Chen R, Rato C, Yan Y, Crespillo-Casado A, Clarke HJ, Harding HP, Marciniak SJ*, Read RJ*, Ron D*. [*joint senior]. Elife. 2015 Mar 16;4. doi: 10.7554/eLife.04871. [Epub ahead of print]
A single-chain variable fragment intrabody prevents intracellular polymerization of Z α1-antitrypsin while allowing its antiproteinase activity.
Ordóñez A, Pérez J, Tan L, Dickens JA, Motamedi-Shad N, Irving JA, Haq I, Ekeowa U, Marciniak SJ, Miranda E, Lomas DA. FASEB J. 2015 Mar 10. pii: fj.14-267351. [Epub ahead of print]

Characterising the association of latency with α(1)-antitrypsin polymerisation using a novel monoclonal antibody.
Tan L, Perez J, Mela M, Miranda E, Burling KA, Rouhani FN, DeMeo DL, Haq I, Irving JA, Ordóñez A, Dickens JA, Brantly M, Marciniak SJ, Alexander GJ, Gooptu B, Lomas DA.
Int J Biochem Cell Biol. 2015 Jan;58:81-91. doi: 10.1016/j.biocel.2014.11.005. Epub 2014 Nov 13.

Function of monocytes and monocyte-derived macrophages in α1-antitrypsin deficiency.
Van't Wout EF, van Schadewijk A, Lomas DA, Stolk J, Marciniak SJ, Hiemstra PS.
Eur Respir J. 2015 Feb;45(2):365-76. doi: 10.1183/09031936.00046114. Epub 2014 Oct 16.
Defining dysfunctional α1-antitrypsin conformers in vitro, in vivo and in therapeutics. Tan L., Perez J., Gooptu B., Mela M., Miranda E., Burling K.A., RouhaniMarciniak S.J., Alexander G., Gooptu B., Lomas D.A., (2015)  Int J Biochem Cell Biol. 58:81-91.

2014 Papers


The TRiC/CCT Chaperone Is Implicated in Alzheimer's Disease Based on Patient GWAS and an RNAi Screen in Aβ-Expressing Caenorhabditis elegans. Khabirova E., Moloney A., Marciniak S.J., Williams J., Lomas D.A., Oliver S.G., Favrin G., Sattelle D.B., Crowther D.C. (2014).    PLoS One. 2014 Jul 31;9(7):e102985. doi: 10.1371/journal.pone.0102985.eCollection 2014.

Palliative treatment for symptomatic malignant pericardial effusion. Jama G.M., Scarci M., Bowden J., & Marciniak S.J. (2014)  Interact Cardiovasc Thorac Surg. 2014 Dec;19(6):1019-26. doi: 10.1093/icvts/ivu267. Epub 2014 Aug 20.

Protein misfolding and ER stress. Chambers JE, Marciniak SJ. Am J Physiol Cell Physiol. 2014 Jun 18. pii: ajpcell.00183.2014. [Epub ahead of print] PMID: 24944205

 Endoplasmic reticulum stress in malignancy. Clarke HJ, Chambers JE, Liniker E, Marciniak SJ. Cancer Cell. 2014 May 12;25(5):563-73. doi: 10.1016/j.ccr.2014.03.015. PMID: 24823636

The unfolded protein response governs integrity of the haematopoietic stem-cell pool during stress. van Galen P, Kreso A, Mbong N, Kent DG, Fitzmaurice T, Chambers JE, Xie S, Laurenti E, Hermans K, Eppert K, Marciniak SJ, Goodall JC, Green AR, Wouters BG, Wienholds E, Dick JE. Nature. 2014 Jun 12;510(7504):268-72. doi: 10.1038/nature13228. Epub 2014 Apr 28. PMID: 24776803

The integrated stress response in lung disease. van ‘t Wout EF, Hiemstra PS, Marciniak SJ. Am J Respir Cell Mol Biol. 2014 Jun;50(6):1005-9. doi: 10.1165/rcmb.2014-0019TR. PMID: 24605820

 Circulating polymers in α1-antitrypsin deficiency. Tan L, Dickens JA, Demeo DL, Miranda E, Perez J, Rashid ST, Day J, Ordoñez A, Marciniak SJ, Haq I, Barker AF, Campbell EJ, Eden E, McElvaney NG, Rennard SI, Sandhaus RA, Stocks JM, Stoller JK, Strange C, Turino G, Rouhani FN, Brantly M, Lomas DA. Eur Respir J. 2014 May;43(5):1501-4. doi: 10.1183/09031936.00111213. Epub 2014 Mar 6.  PMID: 24603821

 Genetic susceptibility. Marciniak SJ, Lomas DA. Clin Chest Med. 2014 Mar;35(1):29-38. doi: 10.1016/j.ccm.2013.10.008. Epub 2013 Dec 12. PMID: 24507835

Increased ERK signalling promotes inflammatory signalling in primary airway epithelial cells expressing Z α1-antitrypsin. van ‘t Wout EF, Dickens JA, van Schadewijk A, Haq I, Kwok HF, Ordóñez A, Murphy G, Stolk J, Lomas DA, Hiemstra PS, Marciniak SJ. Hum Mol Genet. 2014 Feb 15;23(4):929-41. doi: 10.1093/hmg/ddt487. Epub 2013 Oct 4. PMID: 24097797

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