المؤلفون: Hurcombe, J A, Hartley, P, Lay, A C, Ni, L, Bedford, J J, Leader, J P, Singh, S, Murphy, A, Scudamore, C L, Marquez, E, Barrington, A F, Pinto, V, Marchetti, M, Wong, Liang-Fong, Uney, J, Saleem, M A, Mathieson, P W, Patel, S, Walker, R J, Woodgett, J R, Quaggin, S E, Welsh, G I, Coward, R J M

المصدر: Hurcombe , J A , Hartley , P , Lay , A C , Ni , L , Bedford , J J , Leader , J P , Singh , S , Murphy , A , Scudamore , C L , Marquez , E , Barrington , A F , Pinto , V , Marchetti , M , Wong , L-F , Uney , J , Saleem , M A , Mathieson , P W , Patel , S , Walker , R J , Woodgett , J R , Quaggin , S E , Welsh , G I ....

الوصف: Albuminuria affects millions of people, and is an independent risk factor for kidney failure, cardiovascular morbidity and death. The key cell that prevents albuminuria is the terminally differentiated glomerular podocyte. Here we report the evolutionary importance of the enzyme Glycogen Synthase Kinase 3 (GSK3) for maintaining podocyte function in mice and the equivalent nephrocyte cell in Drosophila. Developmental deletion of both GSK3 isoforms (α and β) in murine podocytes causes late neonatal death associated with massive albuminuria and renal failure. Similarly, silencing GSK3 in nephrocytes is developmentally lethal for this cell. Mature genetic or pharmacological podocyte/nephrocyte GSK3 inhibition is also detrimental; producing albuminuric kidney disease in mice and nephrocyte depletion in Drosophila. Mechanistically, GSK3 loss causes differentiated podocytes to re-enter the cell cycle and undergo mitotic catastrophe, modulated via the Hippo pathway but independent of Wnt-β-catenin. This work clearly identifies GSK3 as a critical regulator of podocyte and hence kidney function.

وصف الملف: application/pdf

العلاقة: https://research-information.bris.ac.uk/en/publications/1e33d596-640f-4b93-80ac-7eb45b207c26Test

الإتاحة: https://doi.org/10.1038/s41467-018-08235-1Test
https://hdl.handle.net/1983/1e33d596-640f-4b93-80ac-7eb45b207c26Test
https://research-information.bris.ac.uk/en/publications/1e33d596-640f-4b93-80ac-7eb45b207c26Test
https://research-information.bris.ac.uk/ws/files/184078072/s41467_018_08235_1.pdfTest
https://research-information.bris.ac.uk/ws/files/179329755/Final_Hurcombe_et_al_Nat_Comm_supplementary_information_.pdfTest
http://www.scopus.com/inward/record.url?scp=85060551652&partnerID=8YFLogxKTest

المؤلفون: Hurcombe, Jenny, Lay, Abigail, Ni, Lan, Barrington, Fern, Woodgett, J R, Quaggin, Susan E, Welsh, Gavin, Coward, Richard

المصدر: Hurcombe , J , Lay , A , Ni , L , Barrington , F , Woodgett , J R , Quaggin , S E , Welsh , G & Coward , R 2019 , ' Podocyte GSK3α is important for autophagy and its loss detrimental for glomerular function ' , FASEB BioAdvances , vol. 1 , no. 8 , pp. 498-510 . https://doi.org/10.1096/fba.2019-00011Test

مصطلحات موضوعية: Diabetic nephropathy, insulin signaling, Adriamycin nephropathy, albuminuria

الوصف: Podocytes are key cells in maintaining the integrity of the glomerular filtration barrier and preventing albuminuria. Glycogen synthase kinase 3 (GSK3) is a multi-functional serine/threonine kinase existing as two distinct but related isoforms (α and β). In the podocyte it has previously been reported that inhibition of the β isoform is beneficial in attenuating a variety of glomerular disease models but loss of both isoforms is catastrophic. However, it is not known what the role of GSK3α is in these cells. We now show that GSK3α is present and dynamically modulated in podocytes. When GSK3α is transgenically knocked down specifically in the podocytes of mice it causes mild but significant albuminuria by 6-weeks of life. Its loss also does not protect in models of diabetic or Adriamycin-induced nephropathy. In vitro deletion of podocyte GSK3α causes cell death and impaired autophagic flux suggesting it is important for this key cellular process. Collectively this work shows that GSK3α is important for podocyte health and that augmenting its function may be beneficial in treating glomerular disease.

وصف الملف: application/pdf

الإتاحة: https://doi.org/10.1096/fba.2019-00011Test
https://hdl.handle.net/1983/99913075-fbce-4f64-9313-28662d327a52Test
https://research-information.bris.ac.uk/en/publications/99913075-fbce-4f64-9313-28662d327a52Test
https://research-information.bris.ac.uk/ws/files/205917854/Hurcombe_et_al_2019_FASEB_BioAdvances.pdfTest

المؤلفون: Dembowy, J, Adissu, H A, Liu, J C, Zacksenhaus, E, Woodgett, J R

المصدر: Oncogene ; volume 34, issue 27, page 3514-3526 ; ISSN 0950-9232 1476-5594

مصطلحات موضوعية: Cancer Research, Genetics, Molecular Biology

الإتاحة: https://doi.org/10.1038/onc.2014.279Test
http://www.nature.com/articles/onc2014279.pdfTest
http://www.nature.com/articles/onc2014279Test

المؤلفون: O'BRIEN W. T., HARPER A. D., JOVE F., WOODGETT J. R., MARETTO S., KLEIN P. S., PICCOLO, STEFANO

المساهمون: O'Brien, W. T., Harper, A. D., Jove, F., Woodgett, J. R., Maretto, S., Piccolo, Stefano, Klein, P. S.

الوصف: Lithium is widely used to treat bipolar disorder, but its mechanism of action in this disorder is unknown. Several molecular targets of lithium have been identified, but these putative targets have not been shown to be responsible for the behavioral effects of lithium in vivo. A robust model for the effects of chronic lithium on behavior in mice would greatly facilitate the characterization of lithium action. We describe behaviors in mice that are robustly affected by chronic lithium. Remarkably, these lithium-sensitive behaviors are also observed in mice lacking one copy of the gene encoding glycogen synthase kinase-3beta (Gsk-3beta), a well established direct target of lithium. In addition, chronic lithium induces molecular changes consistent with inhibition of GSK-3 within regions of the brain that are paralleled in Gsk-3beta+/- heterozygous mice. We also show that lithium therapy activates Wnt signaling in vivo, as measured by increased Wnt-dependent gene expression in the amygdala, hippocampus, and hypothalamus. These observations support a central role for GSK-3beta in mediating behavioral responses to lithium.

العلاقة: info:eu-repo/semantics/altIdentifier/pmid/15282284; info:eu-repo/semantics/altIdentifier/wos/WOS:000222950400021; volume:24; firstpage:6791; lastpage:6798; journal:THE JOURNAL OF NEUROSCIENCE; http://hdl.handle.net/11577/1480617Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-3342955475

الإتاحة: https://doi.org/10.1523/JNEUROSCI.4753-03.2004Test
http://hdl.handle.net/11577/1480617Test

المؤلفون: Ling, L S, Voskas, D, Woodgett, J R

المصدر: Oncogene ; volume 32, issue 47, page 5397-5408 ; ISSN 0950-9232 1476-5594

مصطلحات موضوعية: Cancer Research, Genetics, Molecular Biology

الإتاحة: https://doi.org/10.1038/onc.2013.44Test
http://www.nature.com/articles/onc201344.pdfTest
http://www.nature.com/articles/onc201344Test

المؤلفون: Woodgett, J. R.

المصدر: JNCI Journal of the National Cancer Institute ; volume 104, issue 10, page 722-723 ; ISSN 0027-8874 1460-2105

الإتاحة: https://doi.org/10.1093/jnci/djs223Test
http://academic.oup.com/jnci/article-pdf/104/10/722/7674817/djs223.pdfTest

المؤلفون: Garzia L., Kijima N., Morrissy A. S., De Antonellis P., Guerreiro-Stucklin A., Holgado B. L., Wu X., Wang X., Parsons M., Zayne K., Manno A., Kuzan-Fischer C., Nor C., Donovan L. K., Liu J., Qin L., Garancher A., Liu K. -W., Mansouri S., Luu B., Thompson Y. Y., Ramaswamy V., Peacock J., Farooq H., Skowron P., Shih D. J. H., Li A., Ensan S., Robbins C. S., Cybulsky M., Mitra S., Ma Y., Moore R., Mungall A., Cho Y. -J., Weiss W. A., Chan J. A., Hawkins C. E., Massimino M., Jabado N., Zapotocky M., Sumerauer D., Bouffet E., Dirks P., Tabori U., Sorensen P. H. B., Brastianos P. K., Aldape K., Jones S. J. M., Marra M. A., Woodgett J. R., Wechsler-Reya R. J., Fults D. W., Taylor M. D.

المساهمون: Garzia, L., Kijima, N., Morrissy, A. S., De Antonellis, P., Guerreiro-Stucklin, A., Holgado, B. L., Wu, X., Wang, X., Parsons, M., Zayne, K., Manno, A., Kuzan-Fischer, C., Nor, C., Donovan, L. K., Liu, J., Qin, L., Garancher, A., Liu, K. -W., Mansouri, S., Luu, B., Thompson, Y. Y., Ramaswamy, V., Peacock, J., Farooq, H., Skowron, P., Shih, D. J. H., Li, A., Ensan, S., Robbins, C. S., Cybulsky, M., Mitra, S., Ma, Y., Moore, R., Mungall, A., Cho, Y. -J., Weiss, W. A., Chan, J. A., Hawkins, C. E., Massimino, M., Jabado, N., Zapotocky, M., Sumerauer, D., Bouffet, E., Dirks, P., Tabori, U., Sorensen, P. H. B., Brastianos, P. K., Aldape, K., Jones, S. J. M., Marra, M. A., Woodgett, J. R., Wechsler-Reya, R. J., Fults, D. W., Taylor, M. D.

الوصف: (Cell 172, 1050–1062; February 22, 2018) It has come to our attention that in preparing the final version of the manuscript, we made a mistake in the legend for Figure 6. The figure includes 4 major panels labeled A, B, C and D, and we inadvertently included descriptions for panels A, B, C, D, and E. The information in the Figure 6E legend describes panel 6D and should have been labeled as such, and the text labeled 6D should have been deleted. The error has been corrected online, and we apologize for any confusion we may have caused.

العلاقة: volume:173; issue:6; firstpage:1549; journal:CELL; https://hdl.handle.net/11588/900833Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85047212452

الإتاحة: https://doi.org/10.1016Test/j.cell.2018.05.033
https://hdl.handle.net/11588/900833Test

المؤلفون: Garzia L., Kijima N., Morrissy A. S., De Antonellis P., Guerreiro-Stucklin A., Holgado B. L., Wu X., Wang X., Parsons M., Zayne K., Manno A., Kuzan-Fischer C., Nor C., Donovan L. K., Liu J., Qin L., Garancher A., Liu K. -W., Mansouri S., Luu B., Thompson Y. Y., Ramaswamy V., Peacock J., Farooq H., Skowron P., Shih D. J. H., Li A., Ensan S., Robbins C. S., Cybulsky M., Mitra S., Ma Y., Moore R., Mungall A., Cho Y. -J., Weiss W. A., Chan J. A., Hawkins C. E., Massimino M., Jabado N., Zapotocky M., Sumerauer D., Bouffet E., Dirks P., Tabori U., Sorensen P. H. B., Brastianos P. K., Aldape K., Jones S. J. M., Marra M. A., Woodgett J. R., Wechsler-Reya R. J., Fults D. W., Taylor M. D.

المساهمون: Garzia, L., Kijima, N., Morrissy, A. S., De Antonellis, P., Guerreiro-Stucklin, A., Holgado, B. L., Wu, X., Wang, X., Parsons, M., Zayne, K., Manno, A., Kuzan-Fischer, C., Nor, C., Donovan, L. K., Liu, J., Qin, L., Garancher, A., Liu, K. -W., Mansouri, S., Luu, B., Thompson, Y. Y., Ramaswamy, V., Peacock, J., Farooq, H., Skowron, P., Shih, D. J. H., Li, A., Ensan, S., Robbins, C. S., Cybulsky, M., Mitra, S., Ma, Y., Moore, R., Mungall, A., Cho, Y. -J., Weiss, W. A., Chan, J. A., Hawkins, C. E., Massimino, M., Jabado, N., Zapotocky, M., Sumerauer, D., Bouffet, E., Dirks, P., Tabori, U., Sorensen, P. H. B., Brastianos, P. K., Aldape, K., Jones, S. J. M., Marra, M. A., Woodgett, J. R., Wechsler-Reya, R. J., Fults, D. W., Taylor, M. D.

مصطلحات موضوعية: brain tumor, circulating tumor cell, medulloblastoma, metastase, pediatric cancer, Allograft, Animal, Cell Line, Tumor, Chemokine CCL2, Chromosomes, Human, Pair 10, Female, Male, Meningeal Neoplasm, Mice, SCID, Neoplastic Cells, Circulating, Parabiosis

الوصف: While the preponderance of morbidity and mortality in medulloblastoma patients are due to metastatic disease, most research focuses on the primary tumor due to a dearth of metastatic tissue samples and model systems. Medulloblastoma metastases are found almost exclusively on the leptomeningeal surface of the brain and spinal cord; dissemination is therefore thought to occur through shedding of primary tumor cells into the cerebrospinal fluid followed by distal re-implantation on the leptomeninges. We present evidence for medulloblastoma circulating tumor cells (CTCs) in therapy-naive patients and demonstrate in vivo, through flank xenografting and parabiosis, that medulloblastoma CTCs can spread through the blood to the leptomeningeal space to form leptomeningeal metastases. Medulloblastoma leptomeningeal metastases express high levels of the chemokine CCL2, and expression of CCL2 in medulloblastoma in vivo is sufficient to drive leptomeningeal dissemination. Hematogenous dissemination of medulloblastoma offers a new opportunity to diagnose and treat lethal disseminated medulloblastoma. In addition to disseminating through the cerebrospinal fluid, medulloblastoma can metastasize through circulating tumor cells in the blood, thereby providing a different angle for clinical diagnosis and treatment development.

العلاقة: volume:172; issue:5; firstpage:1050; lastpage:1062.e14; journal:CELL; https://hdl.handle.net/11588/900695Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85042368937

الإتاحة: https://doi.org/10.1016Test/j.cell.2018.01.038
https://hdl.handle.net/11588/900695Test

المؤلفون: Salahshor, S, Woodgett, J R

مصطلحات موضوعية: Reviews

الوصف: The products of the two mammalian Axin genes (Axin1 and its homologue Axin2) are essential for the degradation of β catenin, a component of Wnt signalling that is frequently dysregulated in cancer cells. Axin is a multidomain scaffold protein that has many functions in biological signalling pathways. Overexpression of axin results in axis duplication in mouse embryos. Wnt signalling activity determines dorsal–ventral axis formation in vertebrates, implicating axin as a negative regulator of this signalling pathway. In addition, Wnts modulate pattern formation and the morphogenesis of most organs by influencing and controlling cell proliferation, motility, and fate. Defects in different components of the Wnt signalling pathway promote tumorigenesis and tumour progression. Recent biochemical studies of axins indicate that these molecules are the primary limiting components of this pathway. This review explores the intriguing connections between defects in axin function and human diseases.

وصف الملف: text/html

العلاقة: http://jcp.bmj.com/cgi/content/short/58/3/225Test; http://dx.doi.org/10.1136/jcp.2003.009506Test

الإتاحة: https://doi.org/10.1136/jcp.2003.009506Test
http://jcp.bmj.com/cgi/content/short/58/3/225Test

المؤلفون: Hansen, L., Arden, K. C., Rasmussen, S. B., Viars, C. S., Vestergaard, H., Hansen, T., Møller, A. M., Woodgett, J. R., Pedersen, O.

المصدر: Diabetologia ; volume 40, issue 8, page 940-946 ; ISSN 0012-186X 1432-0428

مصطلحات موضوعية: Endocrinology, Diabetes and Metabolism, Internal Medicine

الإتاحة: https://doi.org/10.1007/s001250050771Test