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Wallenius, Anders
Publications (7 of 7) Show all publications
Wallenius, A., Hauser, J., Aas, P. A., Sarno, A., Kavli, B., Krokan, H. E. & Grundström, T. (2014). Expression and recruitment of uracil-DNA glycosylase are regulated by E2A during antibody diversification. Molecular Immunology, 60(1), 23-31
Open this publication in new window or tab >>Expression and recruitment of uracil-DNA glycosylase are regulated by E2A during antibody diversification
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2014 (English)In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 60, no 1, p. 23-31Article in journal (Refereed) Published
Abstract [en]

B-lymphocytes can modify their immunoglobulin (Ig) genes to generate specific antibodies with a new isotype and enhanced affinity against an antigen. Activation-induced cytidine deaminase (AID), which is positively regulated by the transcription factor E2A, is the key enzyme that initiates these processes by deaminating cytosine to uracil in Ig genes. Nuclear uracil-DNA glycosylase (UNG2) is subsequently required for uracil processing in the generation of high affinity antibodies of different isotypes. Here we show that the transcription factor E2A binds to the UNG2 promoter and represses UNG2 expression. Inhibition of E2A by binding of Ca2+-activated calmodulin alleviates this repression. Furthermore, we demonstrate that UNG2 preferentially accumulates in regions of the Ig heavy chain (IgH) gene containing AID hotspots. Calmodulin inhibition of E2A strongly enhances this UNG2 accumulation, indicating that it is negatively regulated by E2A as well. We show also that over-expression of E2A can suppress class switch recombination. The results suggest that E2A is a key factor in regulating the balance between AID and UNG2, both at expression and Ig targeting levels, to stimulate Ig diversification and suppress normal DNA repair processes. (c) 2014 Elsevier Ltd. All rights reserved.

Keywords
B cells, Cell differentiation, Antibodies, Gene regulation, Transcription factors
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-90404 (URN)10.1016/j.molimm.2014.03.011 (DOI)000336473200004 ()2-s2.0-84898920232 (Scopus ID)
Available from: 2014-07-10 Created: 2014-06-23 Last updated: 2023-03-24Bibliographically approved
Gudey, S. K., Wallenius, A. & Landström, M. (2014). Regulated intramembrane proteolysis of the TGF beta type I receptor conveys oncogenic signals. Future Oncology, 10(11), 1853-1861
Open this publication in new window or tab >>Regulated intramembrane proteolysis of the TGF beta type I receptor conveys oncogenic signals
2014 (English)In: Future Oncology, ISSN 1479-6694, E-ISSN 1744-8301, Vol. 10, no 11, p. 1853-1861Article in journal (Refereed) Published
Abstract [en]

Cancer cells produce high levels of TGF beta, a multipotent cytokine. Binding of TGF beta to its cell surface receptors, the transmembrane serine/threonine kinases T beta RII and T beta RI, causes phosphorylation and activation of intracellular latent Smad transcription factors. Nuclear Smads act in concert with specific transcription factors to reprogram epithelial cells to become invasive mesenchymal cells. TGF beta also propagates non-canonical signals, so it is crucial to have a better understanding of the underlying molecular mechanisms which favor this pathway. Here we highlight our recent discovery that TGF beta promotes the proteolytic cleavage of T beta RI in cancer cells, resulting in the liberation and nuclear translocation of its intracellular domain, acting as co-regulator to transcribe pro-invasive genes. This newly identified oncogenic TGF beta pathway resembles the Notch signaling pathway. We discuss our findings in relation to Notch and provide a short overview of other growth factors that transduce signals via nuclear translocation of their cell surface receptors.

Place, publisher, year, edition, pages
London, UK: Future Medicine Ltd, 2014
Keywords
cancer, nucleus TGF beta, proteolysis, receptors, signal transduction
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-96974 (URN)10.2217/FON.14.45 (DOI)000344058100006 ()2-s2.0-84905901458 (Scopus ID)
Available from: 2014-12-09 Created: 2014-12-05 Last updated: 2023-03-24Bibliographically approved
Hauser, J., Kumar, R., Wallenius, A., Grundström, C., Ahmed, T. & Grundström, T. (2014). Regulation of diversification and affinity maturation of antibodies. International Journal of Molecular Medicine, 34, S50-S50
Open this publication in new window or tab >>Regulation of diversification and affinity maturation of antibodies
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2014 (English)In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 34, p. S50-S50Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Spandidos publishing, 2014
National Category
Basic Medicine
Identifiers
urn:nbn:se:umu:diva-94174 (URN)000341276000184 ()
Note

Supplement 1, Meeting abstract 283

Available from: 2014-10-06 Created: 2014-10-06 Last updated: 2018-06-07Bibliographically approved
Gudey, S. K., Sundar, R., Mu, Y., Wallenius, A., Zang, G., Bergh, A., . . . Landström, M. (2014). TRAF6 stimulates the tumor-promoting effects of TGF beta type I receptor through polyubiquitination and activation of Presenilin 1. Science Signaling, 7(307), Article ID ra2.
Open this publication in new window or tab >>TRAF6 stimulates the tumor-promoting effects of TGF beta type I receptor through polyubiquitination and activation of Presenilin 1
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2014 (English)In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 7, no 307, article id ra2Article in journal (Refereed) Published
Abstract [en]

Transforming growth factor-beta (TGF beta) can be both a tumor promoter and suppressor, although the mechanisms behind the protumorigenic switch remain to be fully elucidated. The TGF beta type I receptor (T beta RI) is proteolytically cleaved in the ectodomain region. Cleavage requires the combined activities of tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) and TNF-alpha-converting enzyme (TACE). The cleavage event occurs selectively in cancer cells and generates an intracellular domain (ICD) of T beta RI, which enters the nucleus to mediate gene transcription. Presenilin 1 (PS1), a gamma-secretase catalytic core component, mediates intramembrane proteolysis of transmembrane receptors, such as Notch. We showed that TGF beta increased both the abundance and activity of PS1. TRAF6 recruited PS1 to the T beta RI complex and promoted lysine-63-linked polyubiquitination of PS1, which activated PS1. Furthermore, PS1 cleaved T beta RI in the transmembrane domain between valine-129 and isoleucine-130, and ICD generation was inhibited when these residues were mutated to alanine. We also showed that, after entering the nucleus, T beta RI-ICD bound to the promoter and increased the transcription of the gene encoding T beta RI. The TRAF6- and PS1-induced intramembrane proteolysis of T beta RI promoted TGF beta-induced invasion of various cancer cells in vitro. Furthermore, when a mouse xenograft model of prostate cancer was treated with the gamma-secretase inhibitor DBZ {(2S)-2-[2-(3,5-difluorophenyl)-acetylamino]-N-(5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b, d]azepin-7-yl)-propionamide}, generation of T beta RI-ICD was prevented, transcription of the gene encoding the proinvasive transcription factor Snail1 was reduced, and tumor growth was inhibited. These results suggest that gamma-secretase inhibitors may be useful for treating aggressive prostate cancer.

Place, publisher, year, edition, pages
American Association for the Advancement of Science, 2014
National Category
Biochemistry and Molecular Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:umu:diva-85774 (URN)10.1126/scisignal.2004207 (DOI)000329401100004 ()2-s2.0-84892389396 (Scopus ID)
Funder
Swedish Research Council, K2010-67X-15284-01-3Swedish Cancer Society, 100303Knut and Alice Wallenberg Foundation, 2012.0090
Available from: 2014-02-13 Created: 2014-02-10 Last updated: 2023-03-24Bibliographically approved
Gustafsson, S., Wallenius, A., Zackrisson, H., Popova, D., Plym Forshell, L. & Jacobsson, S. O. (2013). Effects of cannabinoids and related fatty acids upon the viability of P19 embryonal carcinoma cells. Archives of Toxicology, 87(11), 1939-1951
Open this publication in new window or tab >>Effects of cannabinoids and related fatty acids upon the viability of P19 embryonal carcinoma cells
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2013 (English)In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 87, no 11, p. 1939-1951Article in journal (Refereed) Published
Abstract [en]

Compounds acting on the cannabinoid (CB) receptors are involved in the control of cell fate, and there is an emerging consensus that CBs have anticancer effects. However, the CB-mediated effects are contradictory since some studies suggest stimulatory effects on cancer cell proliferation, and CBs have been shown to stimulate both proliferation and differentiation of other mitotic cells such as stem and progenitor cells. In this study, the concentration-dependent effects of synthetic and endogenous CBs on the viability of mouse P19 embryonal carcinoma (EC) cells have been examined by using fluorescence assays of cell membrane integrity, cell proliferation, oxidative stress, and detection of apoptosis and necrosis. All compounds examined produced a concentration-dependent decrease in cell viability in the micromolar range, with the potent CB receptor agonist HU 210 and the enantiomer HU 211(with no CB receptor activity) being the most potent compounds examined with apparent IC50 values of 1 µM and 0.6 µM, respectively. The endogenous CB anandamide showed similar potency and efficacy as structurally related polyunsaturated fatty acids with no reported activity at the CB receptors. The rapid (within hours) decrease in cell viability induced by the examined CBs suggests cytocidal rather than antiproliferative effects, and is dependent on the plating cell population density with the highest toxicity around 100 cells/mm2. The CB-induced cytotoxicity, that appears to involve CB receptors and the sphingomyelin-ceramide pathway, is a mixture of both apoptosis and necrosis that can be blocked by the antioxidants α-tocopherol and N-acetylcysteine. In conclusion, both synthetic and endogenous CBs, produce seemingly unspecific cytotoxic effects in the P19 EC cells.

Place, publisher, year, edition, pages
Springer Berlin/Heidelberg, 2013
Keywords
cannabinoids, polyunsaturated fatty acids, embryonal carcinoma cells, cytotoxicity, oxidative stress
National Category
Pharmacology and Toxicology
Research subject
biochemical pharmacology
Identifiers
urn:nbn:se:umu:diva-51550 (URN)10.1007/s00204-013-1051-3 (DOI)000325700300005 ()2-s2.0-84885950944 (Scopus ID)
Available from: 2012-01-31 Created: 2012-01-26 Last updated: 2023-03-24Bibliographically approved
Hauser, J., Verma-Gaur, J., Wallenius, A., Grundström, C. & Grundström, T. (2013). Mechanisms controlling diversification and affinity maturation of antibodies. International Journal of Molecular Medicine, 32, S45-S45
Open this publication in new window or tab >>Mechanisms controlling diversification and affinity maturation of antibodies
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2013 (English)In: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 32, p. S45-S45Article in journal, Meeting abstract (Other academic) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-81844 (URN)000324507400162 ()
Available from: 2013-10-22 Created: 2013-10-22 Last updated: 2018-06-08Bibliographically approved
Hauser, J., Verma-Gaur, J., Wallenius, A. & Grundström, T. (2011). Regulatory mechanisms controlling diversification and affinity maturation of antibodies. In: : . Paper presented at 6th World Congress on Advances in Oncology and 14th International Symposium on Molecular Medicine October 6-8, 2011 Hotel Rodos Palace, Rhodes Island, Greece (pp. S46). , 28
Open this publication in new window or tab >>Regulatory mechanisms controlling diversification and affinity maturation of antibodies
2011 (English)Conference paper, Published paper (Refereed)
Series
International Journal of Molecular Medicine, ISSN 1107-3756 ; Vol. 28 Suppl. 1
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-49275 (URN)000295422700167 ()
Conference
6th World Congress on Advances in Oncology and 14th International Symposium on Molecular Medicine October 6-8, 2011 Hotel Rodos Palace, Rhodes Island, Greece
Available from: 2011-11-09 Created: 2011-11-04 Last updated: 2018-06-08Bibliographically approved
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