![Andrew Tee BSc (Hons), PhD](https://profiles-cardiff.imgix.net/attachments/2618?w=200&h=200&auto=format&crop=faces&fit=crop&q=90")
Yr Athro Andrew Tee
(Translated he/him)
BSc (Hons), PhD
Athro
- Sylwebydd y cyfryngau
- Ar gael fel goruchwyliwr ôl-raddedig
Trosolwyg
'Gwneud cyfraniadau mawr at y ddealltwriaeth o'r digwyddiadau cellog i lawr yr afon o mTOR'
Rwy'n defnyddio anhwylderau genetig fel systemau enghreifftiol i ddyrannu mecanweithiau signalau sy'n gysylltiedig â bioleg canser. Drwy ymchwilio i syndromau genetig etifeddol, rwyf wedi cyfrannu at ein dealltwriaeth sylfaenol o glefyd dynol. Yn flaenorol, nodais fod proteinau Tubrous Sclerosis Complex (TSC) yn rhwystro twf tiwmor trwy atal digwyddiadau moleciwlaidd sy'n cynnwys targed mamalaidd / mecanistaidd o rapamycin (mTOR), a arweiniodd wedyn at dreialon clinigol llwyddiannus gan ddefnyddio atalyddion mTOR i drin cleifion Tuberous Sclerosis. Gan fod atalyddion mTOR yn cytostatig, fy ffocws ar hyn o bryd yw ymchwilio i lwybrau therapi eraill i drin Sglerosis Tiwbrous yn well. Fy nod yn y dyfodol yw cymhwyso'r therapïau newydd hyn i ganserau ysbeidiol yn y boblogaeth gyffredinol a hefyd i haenu therapi yn seiliedig ar eneteg a biofarcwyr rhagfynegol. Oherwydd natur amlswyddogaethol atalyddion tiwmor yr wyf yn gweithio arnynt a'r rôl gymhleth y mae mTOR yn ei chwarae yn natblygiad canser, mae diddordebau fy labordy ymchwil yn amrywiol ond yn gysylltiedig yn gynhenid â mecanweithiau signalau sy'n ysgogwyr canser:
- rheoli twf celloedd
- autophagy (ailgylchu cydrannau cellog a rhyngweithio â synhwyro maetholion ac ynni)
- biogenesis/glycolysis mitochondrial (cynhyrchu ynni cellog)
- angiogenesis (twf pibellau gwaed hypoxia)
- Trawsnewid Metabolaidd
- mudo celloedd a goresgyniad
- llid
Arbenigedd signalau: mTOR, Rheb, TSC2, TSC1, FLCN, BHD, HIF, STAT3, NF1, PTEN, NFkB, LKB1 / AMPK, ULK1, S6K1, 4E-BP1, a PGC1alpha.
Mae gweithgarwch uwch mTOR o fewn celloedd yn cyfrannu at batholeg celloedd niweidiol tiwmorau. Mae mTOR yn ymwneud yn ganolog â nifer o syndromau hamartoma etifeddol yr ydym hefyd yn ymchwilio iddynt yn ein labordy ac yn cynnwys: Cymhleth Sglerosis Tuberous (TSC), Birt-Hogg-Dubé (BHD), Neurofibromatosis, a Syndrom Cowden.
Mae'r syndromau genetig etifeddol hyn yn digwydd trwy golli swyddogaeth proteinau atal tiwmor sy'n arwain yn ganlyniadol at weithgarwch uwch o dwf mTOR a thiwmor. Er mwyn deall y clefydau hyn yn well, mae ein labordy yn nodi ac yn nodweddu proteinau a reoleiddir gan mTOR sy'n gyrru ffurfio tiwmorau.
Safleoedd Rhwydwaith Proffesiynol:
- ResearchGate: https://www.researchgate.net/profile/Andrew_Tee
- LinkedIn: https://www.linkedin.com/profile/view?id=305047669
Cyllid Ymchwil:
Cymdeithas Sglerosis Tuberous, Cynghrair Sglerosis Tuberous, Ymddiriedolaeth Myrovlytis, AICR (Ymchwil Canser y Byd bellach), Fferyllol GW, Cronfa Sadwrn yr Ysbyty, Tenovus Cymru, Ymchwil Canser Cymru, ac Ymchwil Iechyd a Gofal Cymru.
Cydweithio diwydiannol:
Fferyllol Apexian a GW / JAZZ Pharmaceuticals
Aelodau presennol o'r Lab:
- Dr Darius McPhail, cymrawd ymchwil ôl-ddoethurol (Ymchwil Canser Cymru)
- Dr Brian Calver, Technegydd Ymchwil (cyllid cysylltiedig gan GW Pharmaceuticals)
- Mr Mohammad Alzahrani, myfyriwr PhD, (Coleg Diogelwch Brenin Fahd / Y Weinyddiaeth Tu / Saudi Arabia)
- Miss Samia Alzahrani, myfyriwr PhD
Aelodau diweddar:
- Dr Jesse Champion, myfyriwr PhD, (Cymdeithas Sglerosis Tuberous)
- Dr Sara Seifan, myfyriwr PhD ac Ymchwil sy'n Gysylltiedig (Ymddiriedolaeth Myrovlytis, a Chynhyrchion Fferyllol GW)
- Dr Ellie Rad, myfyriwr PhD ac Ymchwil sy'n Gysylltiedig (Canolfan Ymchwil Canser Cymru a GW Pharmaceuticals)
- Dr Charlie Johnson, cymrawd ôl-ddoethurol (Ymchwil Canser Cymru)
- Rachel-Ann Russel, myfyriwr PhD (Myfyriwr Tenovus Cymru)
- Henry McCann, myfyriwr PhD (Cymdeithas Sglerosis Tuberous)
Cyhoeddiad
2023
- Bhaoighill, M. N., Falcón-Pérez, J. M., Royo, F., Tee, A., Webber, J. and Dunlop, E. 2023. Tuberous Sclerosis Complex cell-derived EVs have an altered protein cargo capable of regulating their microenvironment and have potential as disease biomarkers. Journal of Extracellular Vesicles 12(6), article number: 12336. (10.1002/jev2.12336)
- Baskaran, P. et al. 2023. Phosphorylation of the novel mTOR substrate Unkempt regulates cellular morphogenesis. Journal of Biological Chemistry 299(1), article number: 102788. (10.1016/j.jbc.2022.102788)
2022
- Champion, J. D. et al. 2022. Drug inhibition of redox factor-1 restores hypoxia-driven changes in tuberous sclerosis complex 2 deficient cells. Cancers 14(24), article number: 6195. (10.3390/cancers14246195)
2021
- Zhang, L. et al. 2021. The role of mitochondria-linked fatty-acid uptake-driven adipogenesis in Graves’ Orbitopathy. Endocrinology 162(12), article number: bqab188. (10.1210/endocr/bqab188)
- Vinsland, E. et al. 2021. The zinc finger/RING domain protein Unkempt regulates cognitive flexibility. Scientific Reports 11(1), article number: 16299. (10.1038/s41598-021-95286-y)
- Gampala, S. et al. 2021. Exploring transcriptional regulators Ref-1 and STAT3 as therapeutic targets in malignant peripheral nerve sheath tumours. British Journal of Cancer 124(9), pp. 1566-1580. (10.1038/s41416-021-01270-8)
- Xie, J. et al. 2021. Reciprocal signaling between mTORC1 and MNK2 controls cell growth and oncogenesis. Cellular and Molecular Life Sciences 78(1), pp. 249–270. (10.1007/s00018-020-03491-1)
2020
- Zhang, L. et al. 2020. Distinctive features of orbital adipose tissue (OAT) in Graves' orbitopathy. International Journal of Molecular Sciences 21(23), article number: 9145. (10.3390/ijms21239145)
2019
- McEneaney, L. J. and Tee, A. R. 2019. Finding a cure for tuberous sclerosis complex: from genetics through to targeted drug therapies. Advances in Genetics 103, pp. 91-118. (10.1016/bs.adgen.2018.11.003)
2018
- Bruning, U. et al. 2018. Impairment of angiogenesis by fatty acid synthase inhibition Involves mTOR malonylation. Cell Metabolism 28(6), pp. 866-880. (10.1016/j.cmet.2018.07.019)
- Johnson, C. E. et al. 2018. Loss of tuberous sclerosis complex 2 sensitizes tumors to nelfinavir−bortezomib therapy to intensify endoplasmic reticulum stress-induced cell death. Oncogene 37, pp. 5913-5925. (10.1038/s41388-018-0381-2)
- McCann, H., Johnson, C., Errington, R., Davies, D. M., Dunlop, E. and Tee, A. 2018. Energy stress-mediated cytotoxicity in tuberous sclerosis complex 2-deficient cells with nelfinavir and mefloquine treatment. Cancers 10(10), pp. -., article number: 375. (10.3390/cancers10100375)
- Murray, J. and Tee, A. 2018. Mechanistic Target of Rapamycin (mTOR) in the cancer setting. Cancers 10(6), pp. 168. (10.3390/cancers10060168)
- Tee, A. 2018. The target of rapamycin and mechanisms of cell growth. International Journal of Molecular Sciences 19(3), pp. 880-892. (10.3390/ijms19030880)
- Rad, E., Murray, J. and Tee, A. 2018. Oncogenic signalling through mechanistic Target Of Rapamycin (mTOR): a driver of metabolic transformation and cancer progression. Cancers 10(1) (10.3390/cancers10010005)
2017
- Johnson, C. E. and Tee, A. R. 2017. Exploiting cancer vulnerabilities: mTOR, autophagy, and homeostatic imbalance. Essays in Biochemistry 61(6), pp. 699-710. (10.1042/EBC20170056)
- Dunlop, E. A., Johnson, C., Wiltshire, M., Errington, R. J. and Tee, A. 2017. Targeting protein homeostasis with nelfinavir/salinomycin dual therapy effectively. Oncotarget (10.18632/oncotarget.16232)
2016
- Tee, A. 2016. The benefits of exploiting rare genetic disorders to better understand human health and disease. Seminars in Cell & Developmental Biology 52, pp. 1-2. (10.1016/j.semcdb.2016.03.007)
- Carroll, B. et al. 2016. Control of TSC2-Rheb signaling axis by arginine regulates mTORC1 activity. eLife 5, pp. -., article number: e11058. (10.7554/eLife.11058)
- Rad, E. and Tee, A. 2016. Neurofibromatosis type 1: Fundamental insights into cell signalling and cancer. Seminars in Cell & Developmental Biology 52, pp. 39-46. (10.1016/j.semcdb.2016.02.007)
- Tee, A., Sampson, J. R., Pal, D. K. and Bateman, J. M. 2016. The role of mTOR signalling in neurogenesis, insights from tuberous sclerosis complex. Seminars in Cell and Developmental Biology 52, pp. 12-20. (10.1016/j.semcdb.2016.01.040)
2015
- Upadhyaya, M. et al. 2015. Correlation of copy number changes and gene expression in neurofibromatosis1-associated malignant peripheral nerve sheath tumours [Abstract]. Pediatric Blood and Cancer 62(S4), pp. S152-S152. (10.1002/pbc.25715)
- Zhang, L. et al. 2015. Reversal of pathological features of Graves' orbitopathy by activation of forkhead transcription factors, FOXOs. Journal of Clinical Endocrinology & Metabolism 101(1), pp. 114-122. (10.1210/jc.2015-2932)
- Rad, E., Dodd, K. M., Thomas, L. E., Upadhyaya, M. and Tee, A. 2015. STAT3 and HIF1 signaling drives oncogenic cellular phenotypes in malignant peripheral nerve sheath tumors. Molecular Cancer Research 13(7), pp. 1149. (10.1158/1541-7786.MCR-14-0182)
- Dodd, K. M., Yang, J., Shen, M. H., Sampson, J. R. and Tee, A. R. 2015. mTORC1 drives HIF-1α and VEGF-A signalling via multiple mechanisms involving 4E-BP1, S6K1 and STAT3. Oncogene 34(17), pp. 2239-2250. (10.1038/onc.2014.164)
- Thomas, L. E. et al. 2015. Evaluation of copy number variation and gene expression in neurofibromatosis type-1-associated malignant peripheral nerve sheath tumours. Human Genomics 9(1), article number: 3. (10.1186/s40246-015-0025-3)
2014
- Tee, A. 2014. Fundamental for life: mTOR orchestrates developing biological systems. Seminars in Cell & Developmental Biology 36, pp. 66-67. (10.1016/j.semcdb.2014.10.001)
- Dunlop, E. and Tee, A. 2014. mTOR and autophagy: a dynamic relationship governed by nutrients and energy. Seminars in Cell and Developmental Biology 36, pp. 121-129. (10.1016/j.semcdb.2014.08.006)
- Johnson, C. et al. 2014. Endoplasmic reticulum stress and cell death in mTORC1-overactive cells is induced by nelfinavir and enhanced by chloroquine. Molecular Oncology 9(3), pp. 675-688. (10.1016/j.molonc.2014.11.005)
- Zhang, L. et al. 2014. Possible targets for nonimmunosuppressive therapy of Graves' orbitopathy. Journal of Clinical Endocrinology & Metabolism 99(7), pp. E1183-E1190. (10.1210/jc.2013-4182)
- Yan, M. et al. 2014. The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation. Journal of Clinical Investigation 124(6), pp. 2640-2650. (10.1172/JCI71749)
- Dunlop, E. et al. 2014. FLCN, a novel autophagy component, interacts with GABARAP and is regulated by ULK1 phosphorylation. Autophagy 10(10), pp. 1749-1760. (10.4161/auto.29640)
2013
- Luijten, M. N. H. et al. 2013. Birt–Hogg–Dubé syndrome is a novel ciliopathy. Human Molecular Genetics 22(21), pp. 4383-4397. (10.1093/hmg/ddt288)
- Zhang, J. et al. 2013. A tuberous sclerosis complex signalling node at the peroxisome regulates mTORC1 and autophagy in response to ROS. Nature Cell Biology 15(10), pp. 1186-1195. (10.1038/ncb2822)
- Dhingra, R. et al. 2013. Bidirectional regulation of nuclear factor- B and mammalian target of rapamycin signaling functionally links Bnip3 gene repression and cell survival of ventricular myocytes. Circulation: Heart Failure 6(2), pp. 335-343. (10.1161/CIRCHEARTFAILURE.112.000061)
- Tripathi, D. N., Chowdhury, R., Trudel, L. J., Tee, A., Slack, R. S., Walker, C. L. and Wogan, G. N. 2013. Reactive nitrogen species regulate autophagy through ATM-AMPK-TSC2-mediated suppression of mTORC1. Proceedings of the National Academy of Sciences of the United States of America 110(32), pp. E2950-E2957. (10.1073/pnas.1307736110)
2012
- Tee, A. and Pause, A. 2012. Birt-Hogg-Dubé: tumour suppressor function and signalling dynamics central to folliculin. Familial Cancer 12(3), pp. 367-372. (10.1007/s10689-012-9576-9)
2011
- Dunlop, E. A., Hunt, D. K., Acosta-Jaquez, H. A., Fingar, D. C. and Tee, A. 2011. ULK1 inhibits mTORC1 signaling, promotes multisite Raptor phosphorylation and hinders substrate binding. Autophagy 7(7), pp. 737-747. (10.4161/auto.7.7.15491)
- Preston, R. S. et al. 2011. Absence of the Birt-Hogg-Dubé gene product is associated with increased hypoxia-inducible factor transcriptional activity and a loss of metabolic flexibility. Oncogene 30(10), pp. 1159-1173. (10.1038/onc.2010.497)
- Dunlop, E. A. et al. 2011. Determining the pathogenicity of patient-derived TSC2 mutations by functional characterization and clinical evidence. European Journal of Human Genetics 19(7), pp. 789-795. (10.1038/ejhg.2011.38)
2010
- Scott, C. L., Walker, D. J., Cwiklinski, E., Tait, C., Tee, A. and Land, S. C. 2010. Control of HIF-1α and vascular signaling in fetal lung involves cross talk between mTORC1 and the FGF-10/FGFR2b/Spry2 airway branching periodicity clock. AJP: Lung Cellular and Molecular Physiology 299(4), pp. L455-L471. (10.1152/ajplung.00348.2009)
- Soliman, G. A., Acosta-Jaquez, H. A., Dunlop, E. A., Ekim, B., Maj, N. E., Tee, A. and Fingar, D. C. 2010. mTOR Ser-2481 Autophosphorylation Monitors mTORC-specific Catalytic Activity and Clarifies Rapamycin Mechanism of Action. Journal of Biological Chemistry 285(11), pp. 7866-7879. (10.1074/jbc.M109.096222)
2009
- Dunlop, E. A., Dodd, K. M., Seymour, L. A. and Tee, A. 2009. Mammalian target of rapamycin complex 1-mediated phosphorylation of eukaryotic initiation factor 4E-binding protein 1 requires multiple protein-protein interactions for substrate recognition. Cellular Signalling 21(7), pp. 1073-1084. (10.1016/j.cellsig.2009.02.024)
- Baird, F. E., Bett, K. J., MacLean, C., Tee, A., Hundal, H. S. and Taylor, P. M. 2009. Tertiary active transport of amino acids reconstituted by coexpression of System A and L transporters in Xenopus oocytes. American Journal of Physiology. Endocrinology and Metabolism 297(3), pp. E822-E829. (10.1152/ajpendo.00330.2009)
- Dunlop, E. A. and Tee, A. 2009. Mammalian target of rapamycin complex 1: Signalling inputs, substrates and feedback mechanisms. Cellular Signalling 21(6), pp. 827-835. (10.1016/j.cellsig.2009.01.012)
- Tee, A., Sampson, J. R. and Cheadle, J. P. 2009. Tuberous sclerosis complex. In: Schwab, M. ed. Encyclopedia of Cancer. 2nd ed. Springer
2003
- Tee, A., Manning, B. D., Roux, P. P., Cantley, L. C. and Blenis, J. 2003. Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Current Biology 13(15), pp. 1259-1268. (10.1016/S0960-9822(03)00506-2)
2002
- Tee, A., Fingar, D. C., Manning, B. D., Kwiatkowski, D. J., Cantley, L. C. and Blenis, J. 2002. Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. Proceedings of the National Academy of Sciences 99(21), pp. 13571-13576. (10.1073/pnas.202476899)
- Manning, B. D., Tee, A., Logsdon, M. N., Blenis, J. and Cantley, L. C. 2002. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Molecular Cell 10(1), pp. 151-162. (10.1016/S1097-2765(02)00568-3)
- Tee, A. and Proud, C. G. 2002. Caspase cleavage of initiation factor 4E-binding protein 1 yields a dominant inhibitor of cap-dependent translation and reveals a novel regulatory motif. Molecular and Cellular Biology 22(6), pp. 1674-1683. (10.1128/MCB.22.6.1674-1683.2002)
Articles
- Bhaoighill, M. N., Falcón-Pérez, J. M., Royo, F., Tee, A., Webber, J. and Dunlop, E. 2023. Tuberous Sclerosis Complex cell-derived EVs have an altered protein cargo capable of regulating their microenvironment and have potential as disease biomarkers. Journal of Extracellular Vesicles 12(6), article number: 12336. (10.1002/jev2.12336)
- Baskaran, P. et al. 2023. Phosphorylation of the novel mTOR substrate Unkempt regulates cellular morphogenesis. Journal of Biological Chemistry 299(1), article number: 102788. (10.1016/j.jbc.2022.102788)
- Champion, J. D. et al. 2022. Drug inhibition of redox factor-1 restores hypoxia-driven changes in tuberous sclerosis complex 2 deficient cells. Cancers 14(24), article number: 6195. (10.3390/cancers14246195)
- Zhang, L. et al. 2021. The role of mitochondria-linked fatty-acid uptake-driven adipogenesis in Graves’ Orbitopathy. Endocrinology 162(12), article number: bqab188. (10.1210/endocr/bqab188)
- Vinsland, E. et al. 2021. The zinc finger/RING domain protein Unkempt regulates cognitive flexibility. Scientific Reports 11(1), article number: 16299. (10.1038/s41598-021-95286-y)
- Gampala, S. et al. 2021. Exploring transcriptional regulators Ref-1 and STAT3 as therapeutic targets in malignant peripheral nerve sheath tumours. British Journal of Cancer 124(9), pp. 1566-1580. (10.1038/s41416-021-01270-8)
- Xie, J. et al. 2021. Reciprocal signaling between mTORC1 and MNK2 controls cell growth and oncogenesis. Cellular and Molecular Life Sciences 78(1), pp. 249–270. (10.1007/s00018-020-03491-1)
- Zhang, L. et al. 2020. Distinctive features of orbital adipose tissue (OAT) in Graves' orbitopathy. International Journal of Molecular Sciences 21(23), article number: 9145. (10.3390/ijms21239145)
- McEneaney, L. J. and Tee, A. R. 2019. Finding a cure for tuberous sclerosis complex: from genetics through to targeted drug therapies. Advances in Genetics 103, pp. 91-118. (10.1016/bs.adgen.2018.11.003)
- Bruning, U. et al. 2018. Impairment of angiogenesis by fatty acid synthase inhibition Involves mTOR malonylation. Cell Metabolism 28(6), pp. 866-880. (10.1016/j.cmet.2018.07.019)
- Johnson, C. E. et al. 2018. Loss of tuberous sclerosis complex 2 sensitizes tumors to nelfinavir−bortezomib therapy to intensify endoplasmic reticulum stress-induced cell death. Oncogene 37, pp. 5913-5925. (10.1038/s41388-018-0381-2)
- McCann, H., Johnson, C., Errington, R., Davies, D. M., Dunlop, E. and Tee, A. 2018. Energy stress-mediated cytotoxicity in tuberous sclerosis complex 2-deficient cells with nelfinavir and mefloquine treatment. Cancers 10(10), pp. -., article number: 375. (10.3390/cancers10100375)
- Murray, J. and Tee, A. 2018. Mechanistic Target of Rapamycin (mTOR) in the cancer setting. Cancers 10(6), pp. 168. (10.3390/cancers10060168)
- Tee, A. 2018. The target of rapamycin and mechanisms of cell growth. International Journal of Molecular Sciences 19(3), pp. 880-892. (10.3390/ijms19030880)
- Rad, E., Murray, J. and Tee, A. 2018. Oncogenic signalling through mechanistic Target Of Rapamycin (mTOR): a driver of metabolic transformation and cancer progression. Cancers 10(1) (10.3390/cancers10010005)
- Johnson, C. E. and Tee, A. R. 2017. Exploiting cancer vulnerabilities: mTOR, autophagy, and homeostatic imbalance. Essays in Biochemistry 61(6), pp. 699-710. (10.1042/EBC20170056)
- Dunlop, E. A., Johnson, C., Wiltshire, M., Errington, R. J. and Tee, A. 2017. Targeting protein homeostasis with nelfinavir/salinomycin dual therapy effectively. Oncotarget (10.18632/oncotarget.16232)
- Tee, A. 2016. The benefits of exploiting rare genetic disorders to better understand human health and disease. Seminars in Cell & Developmental Biology 52, pp. 1-2. (10.1016/j.semcdb.2016.03.007)
- Carroll, B. et al. 2016. Control of TSC2-Rheb signaling axis by arginine regulates mTORC1 activity. eLife 5, pp. -., article number: e11058. (10.7554/eLife.11058)
- Rad, E. and Tee, A. 2016. Neurofibromatosis type 1: Fundamental insights into cell signalling and cancer. Seminars in Cell & Developmental Biology 52, pp. 39-46. (10.1016/j.semcdb.2016.02.007)
- Tee, A., Sampson, J. R., Pal, D. K. and Bateman, J. M. 2016. The role of mTOR signalling in neurogenesis, insights from tuberous sclerosis complex. Seminars in Cell and Developmental Biology 52, pp. 12-20. (10.1016/j.semcdb.2016.01.040)
- Upadhyaya, M. et al. 2015. Correlation of copy number changes and gene expression in neurofibromatosis1-associated malignant peripheral nerve sheath tumours [Abstract]. Pediatric Blood and Cancer 62(S4), pp. S152-S152. (10.1002/pbc.25715)
- Zhang, L. et al. 2015. Reversal of pathological features of Graves' orbitopathy by activation of forkhead transcription factors, FOXOs. Journal of Clinical Endocrinology & Metabolism 101(1), pp. 114-122. (10.1210/jc.2015-2932)
- Rad, E., Dodd, K. M., Thomas, L. E., Upadhyaya, M. and Tee, A. 2015. STAT3 and HIF1 signaling drives oncogenic cellular phenotypes in malignant peripheral nerve sheath tumors. Molecular Cancer Research 13(7), pp. 1149. (10.1158/1541-7786.MCR-14-0182)
- Dodd, K. M., Yang, J., Shen, M. H., Sampson, J. R. and Tee, A. R. 2015. mTORC1 drives HIF-1α and VEGF-A signalling via multiple mechanisms involving 4E-BP1, S6K1 and STAT3. Oncogene 34(17), pp. 2239-2250. (10.1038/onc.2014.164)
- Thomas, L. E. et al. 2015. Evaluation of copy number variation and gene expression in neurofibromatosis type-1-associated malignant peripheral nerve sheath tumours. Human Genomics 9(1), article number: 3. (10.1186/s40246-015-0025-3)
- Tee, A. 2014. Fundamental for life: mTOR orchestrates developing biological systems. Seminars in Cell & Developmental Biology 36, pp. 66-67. (10.1016/j.semcdb.2014.10.001)
- Dunlop, E. and Tee, A. 2014. mTOR and autophagy: a dynamic relationship governed by nutrients and energy. Seminars in Cell and Developmental Biology 36, pp. 121-129. (10.1016/j.semcdb.2014.08.006)
- Johnson, C. et al. 2014. Endoplasmic reticulum stress and cell death in mTORC1-overactive cells is induced by nelfinavir and enhanced by chloroquine. Molecular Oncology 9(3), pp. 675-688. (10.1016/j.molonc.2014.11.005)
- Zhang, L. et al. 2014. Possible targets for nonimmunosuppressive therapy of Graves' orbitopathy. Journal of Clinical Endocrinology & Metabolism 99(7), pp. E1183-E1190. (10.1210/jc.2013-4182)
- Yan, M. et al. 2014. The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation. Journal of Clinical Investigation 124(6), pp. 2640-2650. (10.1172/JCI71749)
- Dunlop, E. et al. 2014. FLCN, a novel autophagy component, interacts with GABARAP and is regulated by ULK1 phosphorylation. Autophagy 10(10), pp. 1749-1760. (10.4161/auto.29640)
- Luijten, M. N. H. et al. 2013. Birt–Hogg–Dubé syndrome is a novel ciliopathy. Human Molecular Genetics 22(21), pp. 4383-4397. (10.1093/hmg/ddt288)
- Zhang, J. et al. 2013. A tuberous sclerosis complex signalling node at the peroxisome regulates mTORC1 and autophagy in response to ROS. Nature Cell Biology 15(10), pp. 1186-1195. (10.1038/ncb2822)
- Dhingra, R. et al. 2013. Bidirectional regulation of nuclear factor- B and mammalian target of rapamycin signaling functionally links Bnip3 gene repression and cell survival of ventricular myocytes. Circulation: Heart Failure 6(2), pp. 335-343. (10.1161/CIRCHEARTFAILURE.112.000061)
- Tripathi, D. N., Chowdhury, R., Trudel, L. J., Tee, A., Slack, R. S., Walker, C. L. and Wogan, G. N. 2013. Reactive nitrogen species regulate autophagy through ATM-AMPK-TSC2-mediated suppression of mTORC1. Proceedings of the National Academy of Sciences of the United States of America 110(32), pp. E2950-E2957. (10.1073/pnas.1307736110)
- Tee, A. and Pause, A. 2012. Birt-Hogg-Dubé: tumour suppressor function and signalling dynamics central to folliculin. Familial Cancer 12(3), pp. 367-372. (10.1007/s10689-012-9576-9)
- Dunlop, E. A., Hunt, D. K., Acosta-Jaquez, H. A., Fingar, D. C. and Tee, A. 2011. ULK1 inhibits mTORC1 signaling, promotes multisite Raptor phosphorylation and hinders substrate binding. Autophagy 7(7), pp. 737-747. (10.4161/auto.7.7.15491)
- Preston, R. S. et al. 2011. Absence of the Birt-Hogg-Dubé gene product is associated with increased hypoxia-inducible factor transcriptional activity and a loss of metabolic flexibility. Oncogene 30(10), pp. 1159-1173. (10.1038/onc.2010.497)
- Dunlop, E. A. et al. 2011. Determining the pathogenicity of patient-derived TSC2 mutations by functional characterization and clinical evidence. European Journal of Human Genetics 19(7), pp. 789-795. (10.1038/ejhg.2011.38)
- Scott, C. L., Walker, D. J., Cwiklinski, E., Tait, C., Tee, A. and Land, S. C. 2010. Control of HIF-1α and vascular signaling in fetal lung involves cross talk between mTORC1 and the FGF-10/FGFR2b/Spry2 airway branching periodicity clock. AJP: Lung Cellular and Molecular Physiology 299(4), pp. L455-L471. (10.1152/ajplung.00348.2009)
- Soliman, G. A., Acosta-Jaquez, H. A., Dunlop, E. A., Ekim, B., Maj, N. E., Tee, A. and Fingar, D. C. 2010. mTOR Ser-2481 Autophosphorylation Monitors mTORC-specific Catalytic Activity and Clarifies Rapamycin Mechanism of Action. Journal of Biological Chemistry 285(11), pp. 7866-7879. (10.1074/jbc.M109.096222)
- Dunlop, E. A., Dodd, K. M., Seymour, L. A. and Tee, A. 2009. Mammalian target of rapamycin complex 1-mediated phosphorylation of eukaryotic initiation factor 4E-binding protein 1 requires multiple protein-protein interactions for substrate recognition. Cellular Signalling 21(7), pp. 1073-1084. (10.1016/j.cellsig.2009.02.024)
- Baird, F. E., Bett, K. J., MacLean, C., Tee, A., Hundal, H. S. and Taylor, P. M. 2009. Tertiary active transport of amino acids reconstituted by coexpression of System A and L transporters in Xenopus oocytes. American Journal of Physiology. Endocrinology and Metabolism 297(3), pp. E822-E829. (10.1152/ajpendo.00330.2009)
- Dunlop, E. A. and Tee, A. 2009. Mammalian target of rapamycin complex 1: Signalling inputs, substrates and feedback mechanisms. Cellular Signalling 21(6), pp. 827-835. (10.1016/j.cellsig.2009.01.012)
- Tee, A., Manning, B. D., Roux, P. P., Cantley, L. C. and Blenis, J. 2003. Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Current Biology 13(15), pp. 1259-1268. (10.1016/S0960-9822(03)00506-2)
- Tee, A., Fingar, D. C., Manning, B. D., Kwiatkowski, D. J., Cantley, L. C. and Blenis, J. 2002. Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling. Proceedings of the National Academy of Sciences 99(21), pp. 13571-13576. (10.1073/pnas.202476899)
- Manning, B. D., Tee, A., Logsdon, M. N., Blenis, J. and Cantley, L. C. 2002. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Molecular Cell 10(1), pp. 151-162. (10.1016/S1097-2765(02)00568-3)
- Tee, A. and Proud, C. G. 2002. Caspase cleavage of initiation factor 4E-binding protein 1 yields a dominant inhibitor of cap-dependent translation and reveals a novel regulatory motif. Molecular and Cellular Biology 22(6), pp. 1674-1683. (10.1128/MCB.22.6.1674-1683.2002)
Book sections
- Tee, A., Sampson, J. R. and Cheadle, J. P. 2009. Tuberous sclerosis complex. In: Schwab, M. ed. Encyclopedia of Cancer. 2nd ed. Springer
Ymchwil
Cymhleth Sglerosis Tuberous
Dechreuais ymddiddori mewn TSC yn Harvard, lle roeddwn yn cymryd rhan mewn nifer o astudiaethau allweddol ar reoli mTOR i fyny'r afon trwy inswlin / PI 3-kinase a phrotein kinase B (PKB / Akt), a chan y Rheb protein G bach. Nodais y cynnyrch genynnau TSC, TSC2 fel swbstrad uniongyrchol ar gyfer PKB / Akt yn ogystal â tharged i lawr yr afon o fewn llwybr kinase protein activated mitogen (MAPK). Darganfyddais hefyd fod y heterodimer TSC1/2 yn atal signalau yn benodol trwy mTOR, a bod hyn oherwydd y gweithgaredd GTPase cynyddol tuag at broteinau G bach newydd o'r enw Rheb a RhebL1. Rwy'n cael fy ystyried yn arbenigwr blaenllaw ar Rheb, ac yn y DU, fi yw'r unig ymchwilydd gyda labordy sefydledig sy'n gweithio'n gyfan gwbl ar TSC a mTOR ar lefel protein ac sydd wedi'i glymu'n uniongyrchol â geneteg a chlinigwyr. Datgelodd fy ngwaith dilynol yn y DU fod mTOR yn rheoleiddio gweithgarwch trawsgrifio Ffactor 1alpha Ysgogol Hypoxig (HIF1alpha) yn uniongyrchol, a throsglwyddydd Signal a activator trawsgrifio 3 (STAT3) ac mae'n ymwneud â dilyniant canser mewn TSC. Gyda'i gilydd, datgelodd fy ymchwil ar TSC fod cynhyrchion genynnau TSC1 a TSC2 yn atal twf celloedd trwy ormes mTOR. Yna cyfieithwyd yr ymchwil sylfaenol hon i'r lleoliad clinigol ar gyfer trin cleifion TSC gyda'r defnydd o'r atalydd mTOR, rapamycin. O ganlyniad, cwblhaodd yr Is-adran Canser a Geneteg ym Mhrifysgol Caerdydd dreial clinigol cam II o ddiogelwch ac effeithiolrwydd therapi sirolimus (analog rapamycin) ar gyfer angiomyolipomas arennol mewn cleifion â TSC. Mae fy nghefndir ymchwil bioleg celloedd cryf ar signalau TSC a mTOR yn cyd-fynd yn strategol i'r ymchwil gyfredol ar TSC yn yr adran. Rydym yn gweithio'n agos fel tîm ymchwil TSC gyda chlinigwyr a genetegwyr yng Nghaerdydd i ddod o hyd i fecanweithiau cellog y gellir eu hecsbloetio ar gyfer therapi posibl.
Birt-Hogg-Dubé
Dechreuais ymddiddori mewn BHD hefyd, gan fod y nodweddion a welwyd yn debyg i'r hyn a welir mewn cleifion TSC, ond nid yw swyddogaeth atal tiwmor BHD yn hysbys. Credwn fod BHD yn angenrheidiol ar gyfer cynnal homeostasis celloedd, lle mae colli swyddogaeth BHD yn arwain at gynnydd tiwmor. Rydym hefyd yn credu bod BHD yn ymwneud â dilyniant canserau ysbeidiol. Trwy dechnegau biocemegol a bioleg celloedd, gwnaethom ddatgelu sawl agwedd ar swyddogaeth atal tiwmor BHD yn ddiweddar. Rydym yn gwybod bod BHD yn ymwneud â ciliogenesis ac wrth reoleiddio metaboledd celloedd trwy HIF1alpha, kinase protein sy'n ddibynnol ar AMP (AMPK) ac awtophagy.
Datganiad ymchwil
Trwy ddeall clefydau genetig sylfaenol fel TSC, BHD, ac NF1, mae fy nhîm ymchwil yn gobeithio datgelu strategaethau therapiwtig newydd sydd hefyd yn drosglwyddadwy ar gyfer clefydau dynol eraill.
Cyfraniad i Wyddoniaeth
1] Datgelodd fy nghyfraniad cynnar fel myfyriwr PhD Gwobr Wellcome Trust fod trawssugno signal trwy mTORC1 yn ymwneud yn agos â'r ymateb marwolaeth celloedd ar driniaeth gydag asiantau niweidiol DNA. Datgelodd y gwaith hwn fod mTORC1 o bosibl yn cael ei reoleiddio yn ystod camau cyn-ymrwymiad apoptosis (fel mecanwaith goroesi), ac y gallai triniaeth rapamycin ohirio marwolaeth celloedd a achosir ar ddifrod DNA (y gwaith hwn oedd y cyntaf i ddangos bod rapamycin wedi gwella goroesiad celloedd). Darganfyddais hefyd y motiff RAIP yn N-terminus ffactor cychwyn ewcaryotig 4E-Binding protein 1 (4E-BP1) sy'n cael ei golli trwy hollti mewn modd dibynnol caspase-3. Mae Cleavage o 4E-BP1 yn arwain at ataliad amlwg o gyfieithu sy'n ddibynnol ar gapiau gan nad yw'r isoform clediog o 4E-BP1 bellach yn swbstrad i mTORC1 ac yn rhwymo'n bendant i ac yn ail-wasgu eIF4E. Roedd yr astudiaethau cynnar hyn yn sylfaen ymchwil gadarn ar gyfer fy nghyfraniadau gwyddonol yn y dyfodol o ran mecanweithiau transduction signal mTORC1.
2] Pan oeddwn yn Gymrawd Ôl-ddoethurol Teithio EMBO (yn labordy'r Athro John Blenis yn Harvard), gwnes sawl cyfraniad mawr i ymchwil ynghylch TSC. Roeddwn yn aelod allweddol a oedd yn ymwneud â nifer o astudiaethau cydweithredol ar ddadansoddiad signal o gymhleth suppressor tiwmor TSC1 / TSC2 (nad oedd yn hysbys ar y pryd). Roeddwn yn ymwneud ag ymchwilio i reolaeth i fyny'r afon o mTORC1 gan kinase protein B (PKB / Akt) a TSC1 / TSC2, a chan y Rheb protein G bach. Nodais fod TSC2 hefyd yn darged i lawr yr afon o fewn llwybr kinase protein actifedig mitogen (MAPK). Ers yr astudiaethau arloesol hyn, rwyf wedi bod yn rhan o lawer o astudiaethau cydweithredol i ddeall TSC1 / TSC2 yn well ar lefel protein, gan gynnwys rheoleiddio ei leoleiddio gan PKB/Akt a thargedu is-bwll o TSC1 / TSC2 i'r peroxisome (yr ydym yn credu ei fod yn rheoleiddio homeostasis metabolig).
3] Fel Cymrawd Ymchwil AICR Datblygu Canolradd a Datblygu Gyrfa, darganfyddais sawl mecanwaith signalau celloedd newydd yn ymwneud â TSC, sy'n ymwneud â goroesi celloedd a rheoli mynegiant genynnau. Datgelais fod mTORC1 yn rheoleiddio gweithgarwch trawsgrifio Ffactor 1α Ysgogadwy Hypoxig (HIF1α), sy'n ymwneud yn feirniadol â chynnydd angiogenesis a thiwmor sy'n gysylltiedig â phatholeg TSC. Yn ddiweddarach, gwnaethom ddatgelu bod mTORC1 i fyny'r afon o STAT3, ac mae STAT3 yn angenrheidiol ar gyfer mynegiant genynnau o HIF1α. Mae hwn yn gyfraniad pwysig sy'n datgelu mecanwaith signalau newydd sydd wedi'i gysylltu'n uniongyrchol â signalau angiogenig. Yn dilyn hynny, dangosais hefyd fod signalau aberrant trwy JAK2 / STAT3 a HIF-1α yn gyrru dilyniant tiwmorau o fewn tiwmorau wain nerfau ymylol malaen lluosog (MPNSTs) o gleifion math 1 Neuroffibromatosis, gan nodi y gallai ataliad echel signalau STAT3 / HIF-1α / VEGF-A fod yn strategaeth therapiwtig hyfyw i drin MPNSTs. Trwy sgrinio panel o gyffuriau a gymeradwywyd yn glinigol, darganfyddais hefyd y gall nelfinavir a chloroquine ladd llinellau celloedd diffygiol TSC2 yn ddetholus, gan nodi y gallai targedu straen reticulum endoplasmig ar y cyd ag ataliad lysosomaidd fod yn strategaeth hyfyw i drin cleifion TS.
Rwyf hefyd wedi cyfrannu at ein dealltwriaeth sylfaenol o mTORC1. Darganfyddiad allweddol oedd nodi bod autophagy yn gormesu gweithgaredd mTORC1 yn rymus trwy phosphorylation ULK1-gyfryngol o Raptor, sy'n atal swbstrad mTORC1 rhwymo i Raptor. Fi oedd y cyntaf i ddangos yn bendant bod recriwtiaid Raptor yn swbstradau i mTORC1 ar gyfer trosglwyddo ffosffophospho effeithlon, a chynlluniodd yr assay Raptor bell-orllewinol i nodweddu docio swbstrad mTORC1 i Raptor.
Rwyf wedi gwneud cyfraniadau sylweddol at ddealltwriaeth o anhwylder genetig cysylltiedig i TSC, o'r enw Birt-Hogg-Dubé (BHD), lle rydym wedi nodi sawl mecanwaith newydd o atal tiwmorau o Folliculin (FLCN). Rwyf wedi dangos bod FLCN yn gormesu HIF-1α, lle mae colli FLCN yn achosi trawsnewid metabolaidd o ran gweithgaredd mitochondrial uwch, rhywogaethau ocsigen adweithiol ac actifadu AMPK. Rwyf wedi dangos bod FLCN hefyd yn gweithredu fel gyrrwr autophagy, ar lefel fflwcs autophagosomal ac mae'n swbstrad newydd o ULK1. Roeddwn hefyd yn rhan o'r astudiaeth gydweithredol a ddatgelodd fod syndrom BHD yn ciliopathi newydd, lle mae FLCN yn ymwneud â ciliogenesis.
Bywgraffiad
Addysg a Chymwysterau:
1998 B.Sc. Anrh Biocemeg (i) Prifysgol Dosbarth Cyntaf Dundee (Dundee, Y Deyrnas Unedig)
2001 Ph.D. Biocemeg Prifysgol Dundee (Dundee, Y Deyrnas Unedig)
Trosolwg gyrfa:
2019 - Athro presennol , Prif Ymchwilydd, Is-adran Canser a Geneteg, Prifysgol Caerdydd, y DU.
2017 - 2019 Darllenydd, Prif Ymchwilydd, Is-adran Canser a Geneteg, Prifysgol Caerdydd, y DU.
2012 - 2017 Uwch Ddarlithydd, Prif Ymchwilydd, Is-adran Canser a Geneteg, Prifysgol Caerdydd
2007 - 2012 Darlithydd Ymchwil anghlinigol, Prif Ymchwilydd, Sefydliad Geneteg Feddygol, Prifysgol Caerdydd
2004 - 2007 Ymchwilydd annibynnol, Labordy yr Athro Grahame D. Hardie, Prifysgol Dundee,
2001 - 2004 Cymrawd Ôl-ddoethurol, Labordy yr Athro John Blenis, Ysgol Feddygol Harvard, Boston, MA.
1998 - 2001 Ph.D. myfyriwr, Labordy yr Athro Christopher G. Proud, Prifysgol Dundee
Anrhydeddau a dyfarniadau
2007 - 2013 Cymdeithas Ryngwladol Ymchwil Canser Cymrodoriaeth Datblygu Gyrfa
2004 - 2007 Cymrodoriaeth Ymchwil Ganolradd Sefydliad Prydeinig y Galon
2003 - 2004 Sefydliad Bioleg Moleciwlaidd Ewropeaidd Cymrodoriaeth Ôl-ddoethurol
1998 - 2001 Efrydiaeth Gwobr Ymddiriedolaeth Wellcome
1998 Dosbarth 1af Anrhydedd mewn Biocemeg, Prifysgol Dundee
Aelodaethau proffesiynol
2021 - Ymgynghorydd Gwyddonol Ymddiriedolaeth Myrovlytis
2011 - Ymgynghorydd Gwyddonol Sefydliad Lymffomyomatosis (LAM)
2007 - Ymgynghorydd Gwyddonol Cymdeithas Sglerosis Tuberous
2003 - Pwyllgor Adolygu Grant Cynghrair Tuberous Sclerosis a Chynghorydd Gwyddonol
2003 - Ymgynghorydd Gwyddonol ac Aelod Cymdeithas Cronfa Sadwrn yr Ysbyty
2012 - Aelod o'r Bwrdd Golygyddol ar gyfer Canserau
2012 - Golygydd Gwadd presennol ar gyfer Biochemical Journal
2013 - Golygydd Gwadd ar gyfer Seminarau mewn Bioleg Celloedd a Datblygiadol
2013 - 2016 FindACure Ymgynghorydd Gwyddonol
Contact Details
Themâu ymchwil
Arbenigeddau
- Bioleg celloedd canser
- Therapi canser
- Geneteg canser