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Ms Anna Nitschke
Our broad research focus is on cellular and molecular biology of disease, with an emphasis on cancer biology. Our two major interests are (1) the study of programmed cell death of normal and cancer cells and (2) understanding the regulation of cellular homeostasis by ubiquitination.
Caspase function in apoptosis and cancer cell death
Loretta Dorstyn, Sonia Shalini, Claire Wilson and Joey Puccini
Caspases are cysteine proteases that act as executioners of apoptosis. Having cloned one of the first caspases (caspase-2), our laboratory has an ongoing program in understanding caspase biology, regulation and function. Our current focus is to delineate the in vivo function of caspase-2. Caspase-2 has been shown to function as an initiator caspase and is activated by various apoptotic signals (eg. cytotoxic drugs, UV, DNA damage). Recently we have found a role for caspase-2 in both apoptotic and non-apoptotic signalling pathways including tumour suppression and ageing. We have demonstrated that loss of caspase-2 enhances oncogene-induced cell transformation and augments lymphomagenesis in the EμMyc mouse model. These studies were the first to implicate caspase-2 as a tumour suppressor. Furthermore, we have shown that caspase-2-/- cells have a defective DNA damage response and show genetic instability and aneuploidy. In addition, we have found that caspase-2 deficiency leads to oxidative stress-induced premature aging in mice.
Drosophila as a model to study the mechanisms and regulation of developmentally programmed cell death
Donna Denton, Loretta Dorstyn, May Aung-Htut, Shannon Nicolson and Cindy Xu
Work in our laboratory has taken advantage of the vinegar fly Drosophila melanogaster as a model system to examine the regulation of apoptosis. Many of the apoptotic components and pathways found in mammals are conserved in Drosophila, thus it is a useful model system to study cell death regulation during development. We are particularly interested in studying (1) the regulation and function of caspases, enzymes that mediate apoptosis, during Drosophila development, (2) the role of autophagy and growth arrest in developmental cell death and (3) the transcriptional regulation of cell death genes in response to the steroid hormone, ecdysone.
(2) In recent studies we discovered that the canonical apoptotic pathway, while essential for most PCD, is largely dispensable for developmental PCD in specific tissues. This is most obvious in the larval midgut, which undergoes PCD during metamorphosis. We found that the inhibition of autophagy leads to a delay in midgut removal indicating a potential role for autophagy in midgut PCD. Given that the role of autophagy in cell death is a matter of extensive debate, our discovery that midgut PCD can be delayed by genetically blocking autophagy provides a unique model for delineating this controversy. In this project, we are further exploring this novel mechanism of midgut cell death and the role growth pathways play in regulating it.
(3) During Drosophila metamorphosis obsolete larval tissues are removed by ecdysone-mediated PCD. Ecdysone, a steroid hormone, binds to its heterodimeric receptor EcR/Usp to regulate the expression of components of the cell death machinery, including several caspases. EcR/Usp recruits coactivators that are capable of modifying histones and remodelling chromatin structure. The aim of this project is to understand the role of chromatin remodelling in hormone-mediated transcription of cell death genes.
Nedd4 proteins in physiology and disease
Natasha Boase, Jantina Manning, Alyshea Collaco and Pranay Goel
Collaborators: David Cook (University of Sydney), Philip Poronnik (University of Queensland), Grigori Rychkov (University of Adelaide), Baoli Yang (University of Iowa) and Roger Daly (Garvan Institute)
Aberrations in the ubiquitin system underpin the pathogenesis of many diseases including malignancies, neurodegenerative disorders and channelopathies. Ubiquitin-protein ligases (E3s) determine the substrate specificity of the ubiquitination process. The Nedd4 family of E3s is evolutionarily conserved and required for the ubiquitination of numerous cellular targets involved in processes such as transcription, stability and trafficking of plasma membrane proteins, and the degradation of misfolded proteins. Nedd4 is a gene initially identified in our laboratory. Members of the Nedd4-family can ubiquitinate a range of membrane proteins, resulting in their internalisation and degradation. We have shown that Nedd4, and the closely related protein Nedd4-2, interacts with and ubiquitinates the epithelial sodium channel (ENaC). ENaC is required for sodium absorption across a range of epithelial tissues such as the lungs, colon and kidney and is an important regulator of blood sodium concentration. Ubiquitination of ENaC by Nedd4 and Nedd4-2 leads to its internalisation and degradation. Recently we have shown that Nedd4-2 is a critical in vivo regulator of ENaC in the lung, and that the absence of Nedd4-2 leads to perinatal lethality in mice. Our current focus is to characterise the mechanisms of regulation of ENaC and other ion channels (such as voltage-gated sodium channels) by Nedd4 and Nedd4-2.
In a collaborative study we have recently found that the loss of Nedd4 in mice results in reduced IGF-1 and insulin signalling, reduced growth and neonatal lethality. Nedd4-deficient cells show reduced mitogenic activity. This appears to be due to increased levels of the adaptor protein Grb10 resulting in IGF-1R mislocalization and inhibition of IGF-1 and insulin signalling. We are now studying the mechanism of Grb10 regulation by Nedd4.
Ndfips as regulators of Nedd4 family members
Natalie Foot, Kimberly Mackenzie and Kathryn Mills
Collaborators: Baoli Yang (University of Iowa)
We have identified a number of Nedd4-interacting proteins. Two such proteins are Ndfip1 and Ndfip2, which display Golgi and endosomal localisation, suggestive of a role in protein trafficking. Based on our data, Ndfip1 and Ndfip2 are predicted to function as adaptor proteins that recruit Nedd4 family E3s to their substrates to provide specificity and regulatory complexity to the ubiquitination system.
Selected Recent Publications
Denton D, Chang T-K, Nicolson S, Shravage B, Simin R, Baehrecke EH, Kumar S (2012) Relationship between growth arrest and autophagy in midgut programmed cell death in Drosophila. Cell Death Differ 19: 1299-1307.
Dorstyn L, Puccini J, Shalini S, Nicola M, Moore S, Kumar S (2012) Caspase-2 deficiency promotes aberrant DNA-damage response and genetic instability. Cell Death Differ 19: 1288-1298.
Shalini S, Dorstyn, L, Wilson C, Puccini J, Ho L, Kumar S (2012) Impaired antioxidant defence and accumulation of oxidative stress in caspase-2-deficient mice. Cell Death Differ 19: 1370-1380.
Garrick MD, Zhao L, Roth JA, Jiang H, Feng J, Foot NJ, Dalton H, Kumar S, Garrick LM (2012) Isoform specific regulation of divalent metal (ion) transporter (DMT1) by proteasomal degradation. BioMetals 25: 787-793.
Klionsky DJ et al. (2012) Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes. Autophagy 8: 445-544.
Denton D, Nicolson S, Kumar S (2012) Cell death by autophagy: Facts and apparent artefacts. Cell Death Differ 19: 87-95.
Howitt J, Lackovic J, Low L-H, Naguib A, Macintyre A, Goh C-P, Callaway JK, Hammond V, Thomas T, Dixon M, Putz U, Silke J, Bartlett P, Yang B, Kumar S, Trotman LC, Tan S-S (2012) Ndfip1 regulates nuclear Pten import in vivo to promote neuronal survival following cerebral ischemia. J Cell Biol 196: 29-36.
Dorstyn L, Kumar S (2012) Insect Caspases. In: The Handbook of Proteolytic Enzymes (Rawlings ND & Salvesen G eds.). Elesevier, Oxford, UK. In press.
Foot NJ, Leong YA, Dorstyn LE, Dalton HE, Ho K, Zhao L, Garrick MD, Yang B, Hiwase D, Kumar S (2011) Ndfip1 deficient mice have impaired DMT1 regulation and iron homeostasis. Blood 117: 638-646.
Yuan S, Yu X, Topf M, Dorstyn L, Kumar S, Ludtke SJ, Akey CW (2011) Structure of the Drosophila apoptosome at 6.9Å resolution. Structure 19: 128-140.
Lee I-H, Song S-H, Campbell CR, Kumar S, Cook DI, Dinudom A (2011) Regulation of epithelial Na+ channel by the RH-domain of G protein-coupled receptor kinase (GRK2) and Gaq/11. J. Biol. Chem. 286:19259-19269.
Dalton HE, Denton D, Foot NJ, Ho K, Mills K, Brou C, Kumar S (2011) Drosophila Ndfip is a novel regulator of Notch signaling. Cell Death Differ 18: 1150-1160.
Boase NA, Rychkov, GY, Townley SL, Dinudom A, Candi E, Voss AK, Tsoutsman T, Semsarian C, Melino G, Koentgen F, Cook DI, Kumar S (2011) Respiratory distress and perinatal lethality in Nedd4-2-deficient mice. Nature Communications 2: 287 doi: 10.1038/ncomms1284.
Galluzzi L, Vitale I, Abrams JM, Alnemri ES, Baehrecke EH, Blagosklonny MV, Dawson TM, Dawson VL, El-Deiry WS, Fulda S, Gottlieb E, Green DR, Hengartner MO, Kepp O, Knight RA, Kumar S, Lipton SA, Lu X, Madeo F, Malorni W, Mehlen P, Nuñez G, Peter ME, Piacentini M, Rubinsztein DC, Shi Y, Simon HU, Vandenabeele P, White E, Yuan J, Zhivotovsky B, Melino G, Kroemer G. (2011) Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ doi: 10.1038/cdd.2011.96. [Epub ahead of print]
Manning JA, Kumar S (2010) A potential role for Nedd1 and the centrosome in senescence of mouse embryonic fibroblasts. Cell Death & Disease 1: e35.
Manning JA, Shalini S, Risk JM, Day CL, Kumar S (2010) A direct interaction with NEDD1 regulates g-tubulin recruitment to the centrosome. PLoS ONE 5(3): e9618.
Manning JA, Lewis M, Koblar SA, Kumar S (2010) An essential function for the centrosomal protein NEDD1 in zebrafish development. Cell Death Differ. 17: 1302-1314.
Hiwase DK, White DL, Powell JA, Saunders VA, Zrim SA, Frede AK, Guthridge MA, Lopez AF, D’Andrea RJ, To LB, Melo JV, Kumar S, Hughes TP (2010) Blocking cytokine signaling along with intense Bcr-Abl kinase inhibition induces apoptosis in primary CML progenitors. Leukemia 24: 771-778.
Denton D, Shravage B, Simin R, Baehrecke EH, Kumar S (2010) Larval midgut destruction in Drosophila: Not dependent on caspases but suppressed by the loss of autophagy. Autophagy 6: 163-165.
Yang B, Kumar S (2010) Nedd4 and Nedd4-2: Closely related ubiquitin-protein ligases with distinct physiological functions. Cell Death Differ. 17: 68-77.
Dorstyn L, Kumar S (2009) Putative functions of caspase-2. f1000 Biology Reports 1: 96.
Kumar S (2009) Caspase 2 in apoptosis, DNA damage response and tumor suppression: Enigma no more? Nature Rev. Cancer 9: 897-903.
Denton D, Shravage B, Simin R, Mills K, Berry DL, Baehrecke EH, Kumar S (2009) Autophagy, not apoptosis, is essential for midgut cell death in Drosophila. Current Biology 19: 1741–1746.
Yang B, Kumar S (2009) Nedd4 and Nedd4-2: Closely related ubiquitin-protein ligases with distinct physiological functions. Cell Death Differ. In press. (doi:10.1038/cdd.2009.84)
Howitt J, Putz U, Lackovic J, Doan A, Dorstyn L, Cheng H, Yang B, Chan-Ling T, Silke J, Kumar S, Tan S-S (2009) Divalent metal transporter 1 (DMT1) regulation by Ndfip1 prevents metal toxicity in human neurons. Proc. Natl. Acad. Sci. USA 106:15489-15494.
Kumar S, Dorstyn L (2009) Analyzing caspase activation and caspase activity in apoptotic cells. In: Apoptosis Methods and Protocols (eds. Peter Erhardt and Ambrus Toth). Humana Press Inc. NJ, USA. Methods in Molecular Biology 559: 3-17.
Galluzzi L, Aaronson SA, Abrams J, Alnemri ES, Andrews DW, Ashkenazi A, Baehrecke EH, Bazan NG, Blagosklonny MV, Blomgren K, Borner C, Bredesen DE, Brenner C, Castedo M, Cidlowski JA, Ciechanover A, Cohen GM, De Laurenzi V, Maria RD, Deshmukh M, Dynlacht BD, El-Deiry WS, Fulda S, Garrido C, Golstein P, De Maria R, Deshmukh M, Dynlacht BD, El-Deiry WS, Flavell RA, Fulda S, Garrido C, Golstein P, Gougeon M-L, Green DR, Gronemeyer H, Hajnoczky G, Hardwick JM, Hengartner M, Ichijo H, Jäättelä M, Kepp O, Kimchi A, Klionsky DJ, Knight RA, Kornbluth S, Kumar S, Levine B, Lipton SA, Lugli E, Madeo F, Malorni W, Marine J-C W, Martin SJ, Medema JP, Mehlen P, Melino G, Moll UM, Morselli E, Nagata S, Nicholson DW, Nicotera P, Nuñez G, Oren M, Penninger J, Pervaiz S, Peter ME, Piacentini M, Prehn JHM, Puthalakath H, Rabinovich G, Rizzuto R, Rodrigues CMP, Rubinsztein DC, Rudel T, Scorrano L, Simon H-U, Steller H, Tschopp J, Tsujimoto Y, Vandenabeele P, Vitale I, Vousden KH, Youle RJ, Yuan J, Zhivotovsky B, Kroemer G (2009) Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotes. Cell Death Differ. 16: 1093–1107.
Kochetkova M, Kumar S, McColl S (2009) The chemokine receptors CXCR4 and CCR7 promote metastasis by preventing anoikis in cancer cells. Cell Death Differ. 16: 664-673.
Ho LH, Taylor R, Cakouros D, Dorstyn L, Bouillet P, Kumar S (2009) A tumor suppressor function for caspase-2. Proc. Natl. Acad. Sci. USA 106: 5336-5341.
Rotin D, Kumar S (2009) Physiological functions of the HECT family of ubiquitin ligases. Nature Rev. Mol. Cell Biol. 10: 398-409.
Lee I-H, Campbell CR, Song S-H, Day ML, Kumar S, Cook DI, Dinudom A (2009) The activity of the epithelial sodium channels is regulated by the caveolin-1 via a Nedd4-2 dependent mechanism. J. Biol. Chem. 284: 12663-12669.
Hiwase DK, White DL, Saunders V, Frede A, To LB, Kumar S, Melo JV, Hughes TP (2009) Short term intense Bcr-Abl kinase inhibition with nilotinib is adequate to trigger cell death in BCR-ABL+ cells. Leukemia 23: 1205-1206.
Kroemer G, Galluzzi L, Vandenabeele P, Abrams J, Alnemri ES, Baehrecke EH, Blagosklonny MV, El-Deiry WS, Golstein P, Green DR, Hengartner M, Knight RA, Kumar S, Lipton SA, Malorni W, Nuñez G, Peter ME, Tschopp J, Yuan J, Piacentini M, Zhivotovsky B, Melino G (2009) Classification of cell death: Recommendations of the nomenclature committee on cell death 2009. Cell Death Differ. 16: 3-11.
Dorstyn L, Kumar S (2008) A biochemical analysis of the activation of the Drosophila caspase DRONC. Cell Death Differ. 15: 461-470.
Cao XR, Lill NL, Boase N, Shi PP, Croucher D, Shan H, Qu J, Sweezer EM, Place T, Kirby PA, Daly RJ, Kumar S*, Yang B* (2008) Nedd4 controls animal growth by regulating IGF-1 signaling. Science Signaling 1: ra5. (* joint senior authors).
Ho LH, Dorstyn L, Lambrusco, L, Read SH, Kumar S (2008) Caspase-2 is required for cell death induced by cytoskeletal disruption. Oncogene 27: 3393-3404.
Denton D, Mills K, Kumar S (2008) Methods and protocols for studying cell death in Drosophila. Methods in Enzymology 446: 17-37.
Cakouros D, Mills K, Denton D, Daish T, Paterson A, Kumar S (2008) dLKR/SDH regulates hormone mediated histone arginine methylation and transcription of cell death genes. J. Cell Biol. 182: 481-495.
Manning JA, Colussi PA, Koblar SA, Kumar S (2008) Nedd1 expression as a marker of dynamic centrosomal localization during mouse embryonic development. Histochem. Cell Biol. 129: 751-764.
Hiwase DK, Saunders V, Hewett D, Frede A, Zrim S, Dang P, Eadie L, To LB, Melo J, Kumar S, Hughes TP, White DL (2008) Dasatinib cellular uptake and efflux in CML cells: Therapeutic implications Clin. Cancer Res. 14: 3881-3888.
Schuetz F, Kumar S, Poronnik P, Adams DJ (2008) Regulation of the voltage-gated K+ channels KCNQ2/3 and 3/5 by the serum- and glucocorticoid-regulated kinase (SGK-1). Am. J. Physiol. Cell Physiol. 295: C73-C80.
He Y, Hryciw DH, Carroll ML, Myers SA,Whitbread AK, Kumar S, Poronnik P, Hooper JD (2008) The ubiquitin-protein ligase Nedd4-2 differentially interacts with and regulates members of the Tweety family of chloride ion channels. J. Biol. Chem. 283: 24000-24010.
Foot NJ, Dalton HE, Shearwin-Whyatt LM, Dorstyn L, Tan SS, Yang, B, Kumar S (2008) Regulation of the divalent metal ion transporter DMT1 and iron homeostasis by a ubiquitin-dependent mechanism involving Ndfips and WWP2. Blood 112: 4268-4275.
Putz U, Howitt J, Lackovic J, Foot NJ, Kumar S, Silke J, Tan S-S (2008) Nedd4-family interacting protein 1 (Ndfip1) is required for the exosomal secretion of Nedd4-family proteins. J. Biol. Chem. 283: 32621-32627.
Manning J, Kumar S (2007) NEDD1: Function in microtubule nucleation, spindle assembly and beyond. Int. J. Biochem. Cell Biol. 39: 7-11.
Doumanis J, Dorstyn L, Kumar S (2007) Molecular determinants of the subcellular localization of the Drosophila Bcl-2 homologues DEBCL and BUFFY. Cell Death Differ. 14: 907-915.
Dibbens LM, Ekberg J, Taylor I, Hodgson BL, Conroy S-J, Lensink IL, Kumar S, Zielinski MA, Harkin LA, Sutherland GR, Adams DJ, Berkovic SF, Scheffer IE, Mulley JC, Poronnik P (2007) NEDD4-2 as a candidate susceptibility gene for epileptic photosensitivity. Genes Brain Behav. 6: 750-755.
Kumar S (2007) Caspases and their many biological functions. Cell Death Differ. 14: 1-2.
Ekberg J, Schuetz F, Boase NA, Conroy S-J, Manning J, Kumar S, Poronnik P, Adams DJ (2007) Regulation of the voltage-gated K+ channels KCNQ2/3 and KCNQ3/5 by ubiquitination: Novel role for Nedd4-2. J. Biol. Chem. 282:12135-12142.
Sanchez-Perez A, Kumar S, Cook DI (2007) GRK2 interacts with and phosphorylates Nedd4 and Nedd4-2. Biochem. Biophys. Res. Commun. 359: 611-615.
Lee I-H, Dinudom A, Sanchez-Perez A, Kumar S, Cook DI (2007) Akt mediates the effects of insulin on epithelial sodium channel by inhibiting Nedd4-2. J. Biol. Chem.282: 29866-29873.
Kumar S (2007) Caspase function in programmed cell death. Cell Death Differ. 14: 32-43.
The Molecular Regulation Laboratory provides an outstanding environment for Honours and Postgraduate studies. Some of the available projects are listed here, however if you are interested in any other areas of our research, please contact individual staff members.
1. The role of caspase-2 in specific pathways of apoptosis and tumorigenesis.
(Contact: Dr Loretta Dorstyn, firstname.lastname@example.org
Our ongoing work has made a landmark discovery that the lack of caspase-2 enhances the ability of cells to transform readily and that caspase-2 deficiency increases the potential of tumourigenesis in vivo. Using the mouse Eμ-Myc lymphoma model we found that the loss of even a single allele of caspase-2 resulted in accelerated tumourigenesis, and this was further enhanced in caspase-2-/- mice. The caspase-2-/- cells show increased growth rates, a defective apoptotic response to cell cycle checkpoint regulation and show abnormal cycling following γ-irradiation. These data show that loss of caspase-2 results in an increased ability of cells to acquire a transformed phenotype and become malignant, indicating that caspase-2 is a tumour suppressor protein. This project involves testing whether the tumour suppressor function of caspase-2 is limited to only Myc-induced lymphomagenesis, or is more general. Cellular and molecular studies will dissect out the mechanism by which caspase-2 acts as a tumour suppressor and identify target(s) of caspase-2 that mediate its tumour suppressor function.
2. Cell death regulation during animal development.
(Contact: Dr Donna Denton, email@example.com
We have been utilising Drosophila as an in vivo model to dissect out the mechanisms of developmentally programmed cell death (PCD). Our ongoing studies have led to several seminal findings, including the discovery of the key canonical pathway of PCD involving the caspase Dronc, and the adaptor Ark. We have also discovered a novel potential regulator of caspase activation from a Dronc-interaction screen. This project will now characterise the role of the novel protein in caspase activation and cell death, and identify other potential regulators of caspase activation using a range of molecular, cellular, biochemical and genetic approaches.
3. Role of autophagy in PCD.
(Contact: Dr Donna Denton, firstname.lastname@example.org)
In recent studies we discovered that the Dronc/Ark pathway, while essential for most PCD, is largely dispensable for developmental PCD in specific tissues. This is most obvious in the larval midgut (MG), which undergoes PCD during metamorphosis, and this process is unaffected in dronc and ark mutants. In preliminary studies we have found that the inhibition of autophagy, a caspase-independent mechanism of PCD, leads to a delay in MG removal indicating a potential role for autophagy in MG PCD. Given that the role of autophagy in cell death is a matter of extensive debate, our discovery that MG PCD can be delayed by genetically blocking autophagy provides a unique model for delineating this controversy. We hypothesise that during development PCD utilises caspase-dependent (most tissues), caspase- and autophagy-dependent (e.g. larval salivary glands), and caspase-independent but autophagy-dependent (e.g. midgut) mechanisms. In this project we will delineate the mechanism of midgut cell death by exploring the contribution of caspases and autophagy. The project also aims to define the role of growth signalling in midgut cell death, to determine how growth signals and death signals may be integrated to regulate autophagy. A range of cellular, molecular and genetic approaches will be utilized in these projects. Given the controversial role of autophagy in human disease a better understanding of the regulation of autophagy is important for future treatments of disease.
4. The role of Nedd4 and Nedd4-2 in hypertension and the regulation of sodium channels.
(Contact: Dr Natasha Boase, email@example.com or Dr Jantina Manning, Jantina.Manning@health.sa.gov.au)
Aberrations in the ubiquitin system underpin the pathogenesis of many diseases including cancer, neurodegenerative disorders and channelopathies. The Nedd4 and related ubiquitin ligases (E3s) are required for the ubiquitination of numerous cellular targets involved in processes such as transcription, stability and trafficking of plasma membrane proteins, and the degradation of misfolded proteins. We have shown that Nedd4-2 E3 ubiquitinates the epithelial sodium channel (ENaC). ENaC is required for sodium absorption across a range of epithelial tissues such as the lungs, colon and kidney and is an important regulator of blood sodium concentration and blood pressure. Ubiquitination of ENaC by Nedd4-2 leads to its internalisation and degradation. Our current focus is to characterise the mechanisms of regulation of ENaC by Nedd4-2 in vivo by using Nedd4-2 gene knockout mice. We are also studying the role of Nedd4-2 in regulating additional novel targets. In this project the students will use a range of molecular, cellular and animal techniques.
5. Regulation of animal growth by Nedd4.
(Contact: Dr Natasha Boase, firstname.lastname@example.org)
In a collaborative study with Prof Yang (University of Iowa) we have recently found that the loss of Nedd4 in mice results in reduced IGF-1 and insulin signalling, reduced growth and neonatal lethality. Nedd4-deficient cells show reduced mitogenic activity. This appears to be due to increased levels of the adaptor protein Grb10 resulting in IGF-1R mislocalization and inhibition of IGF-1 and insulin signalling. We are now studying the mechanism of Grb10 regulation by Nedd4. There is evidence to suggest that Nedd4 has additional cellular targets. Thus, we are analysing additional phenotypes that may be associated with the knockout of Nedd4. This project aims to decipher the mechanisms by which Nedd4 controls animal growth and development.
6. The regulation of iron homeostasis by the Nedd4 binding proteins, Ndfip1 and Ndfip2.
(Contact: Dr Hazel Dalton, email@example.com)
Iron homeostasis is a highly regulated process which, if perturbed, leads to a number of disease states such as haemochromatosis or anaemia. Our recent work shows that Ndfips regulate the divalent metal ion transporter DMT1, the primary non-heme iron transporter in mammals. DMT1 interacts with both Ndfip1 and Ndfip2, and this promotes DMT1 ubiquitination and degradation by the Nedd4-family ubiquitin ligase, WWP2. Furthermore the Ndfip1 knockout mice show increased hepatic iron deposition, indicating an essential function of Ndfip1 in iron homeostasis. Our current focus is to further characterise WWP2 and Ndfip knockout mice to provide additional understanding of this novel mechanism of regulating iron transport. Students will carry out iron feeding experiments, tissue analysis for iron deposition and a range of cellular and molecular studies to delineate the regulation of DMT1 by Ndfips and WWP2.Scholarships are available through various sources including those listed below:
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