UV-mediated Regulation of the anti-senescence factor Tbx2

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dc.contributor.authorAbrahams, Amaal
dc.contributor.authorMowla, Shaheen
dc.contributor.authorPARKER, M Iqbal
dc.contributor.authorGoding, Colin R
dc.contributor.authorPrince, Sharon
dc.date.accessioned2021-10-08T07:22:52Z
dc.date.available2021-10-08T07:22:52Z
dc.date.issued2008
dc.description.abstractSeveral lines of evidence have implicated members of the developmentally important T-box gene family in cell cycle regulation and in cancer. Importantly, the highly related T-box factors Tbx2 and Tbx3 can suppress senescence through repressing the cyclin-dependent kinase inhibitors p19(ARF) and p21(WAF1/CIP1/SDII). Furthermore, Tbx2 is up-regulated in several cancers, including melanomas where it was shown to function as an anti-senescence factor, suggesting that this may be one of the mechanisms by which T-box proteins contribute to the oncogenic process. However, very little is known about whether Tbx2 is regulated by p21-mediated stress-induced senescence signaling pathways. In this study, using the MCF-7 breast cancer cell line known to overexpress Tbx2, we show that in response to stress induced by ultraviolet irradiation the Tbx2 protein is specifically phosphorylated by the p38 mitogen-activated protein kinase. Using site-directed mutagenesis and in vitro kinase assays, we have identified serine residues 336, 623, and 675 in the Tbx2 protein as the p38 target sites and show that these sites are phosphorylated in vivo. Importantly, we show by Western blotting, immunofluorescence, and reporter assays that this phosphorylation leads to increased Tbx2 protein levels, predominant nuclear localization of the protein, and an increase in the ability of Tbx2 to repress the p21(WAF1/CIP1/SDII) promoter. These results show for the first time that the ability of Tbx2 to repress the p21 gene is enhanced in response to a stress-induced senescence pathway, which leads to a better understanding of the regulation of the anti-senescence function of Tbx2.
dc.identifier.apacitationAbrahams, A., Mowla, S., PARKER, M. I., Goding, C. R., & Prince, S. (2008). UV-mediated Regulation of the anti-senescence factor Tbx2. <i>The Journal of Biological Chemistry</i>, 283(4), 2223 - 2230. http://hdl.handle.net/11427/35015en_ZA
dc.identifier.chicagocitationAbrahams, Amaal, Shaheen Mowla, M Iqbal PARKER, Colin R Goding, and Sharon Prince "UV-mediated Regulation of the anti-senescence factor Tbx2." <i>The Journal of Biological Chemistry</i> 283, 4. (2008): 2223 - 2230. http://hdl.handle.net/11427/35015en_ZA
dc.identifier.citationAbrahams, A., Mowla, S., PARKER, M.I., Goding, C.R. & Prince, S. 2008. UV-mediated Regulation of the anti-senescence factor Tbx2. <i>The Journal of Biological Chemistry.</i> 283(4):2223 - 2230. http://hdl.handle.net/11427/35015en_ZA
dc.identifier.issn0021-9258
dc.identifier.issn1083-351X
dc.identifier.ris TY - Journal Article AU - Abrahams, Amaal AU - Mowla, Shaheen AU - PARKER, M Iqbal AU - Goding, Colin R AU - Prince, Sharon AB - Several lines of evidence have implicated members of the developmentally important T-box gene family in cell cycle regulation and in cancer. Importantly, the highly related T-box factors Tbx2 and Tbx3 can suppress senescence through repressing the cyclin-dependent kinase inhibitors p19(ARF) and p21(WAF1/CIP1/SDII). Furthermore, Tbx2 is up-regulated in several cancers, including melanomas where it was shown to function as an anti-senescence factor, suggesting that this may be one of the mechanisms by which T-box proteins contribute to the oncogenic process. However, very little is known about whether Tbx2 is regulated by p21-mediated stress-induced senescence signaling pathways. In this study, using the MCF-7 breast cancer cell line known to overexpress Tbx2, we show that in response to stress induced by ultraviolet irradiation the Tbx2 protein is specifically phosphorylated by the p38 mitogen-activated protein kinase. Using site-directed mutagenesis and in vitro kinase assays, we have identified serine residues 336, 623, and 675 in the Tbx2 protein as the p38 target sites and show that these sites are phosphorylated in vivo. Importantly, we show by Western blotting, immunofluorescence, and reporter assays that this phosphorylation leads to increased Tbx2 protein levels, predominant nuclear localization of the protein, and an increase in the ability of Tbx2 to repress the p21(WAF1/CIP1/SDII) promoter. These results show for the first time that the ability of Tbx2 to repress the p21 gene is enhanced in response to a stress-induced senescence pathway, which leads to a better understanding of the regulation of the anti-senescence function of Tbx2. DA - 2008 DB - OpenUCT DP - University of Cape Town IS - 4 J1 - The Journal of Biological Chemistry LK - https://open.uct.ac.za PY - 2008 SM - 0021-9258 SM - 1083-351X T1 - UV-mediated Regulation of the anti-senescence factor Tbx2 TI - UV-mediated Regulation of the anti-senescence factor Tbx2 UR - http://hdl.handle.net/11427/35015 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/35015
dc.identifier.vancouvercitationAbrahams A, Mowla S, PARKER MI, Goding CR, Prince S. UV-mediated Regulation of the anti-senescence factor Tbx2. The Journal of Biological Chemistry. 2008;283(4):2223 - 2230. http://hdl.handle.net/11427/35015.en_ZA
dc.language.isoeng
dc.publisher.departmentDivision of Cell Biology
dc.publisher.facultyFaculty of Health Sciences
dc.sourceThe Journal of Biological Chemistry
dc.source.journalissue4
dc.source.journalvolume283
dc.source.pagination2223 - 2230
dc.source.urihttps://dx.doi.org/10.1074/jbc.M705651200
dc.subject.otherAnimals
dc.subject.otherCercopithecus aethiops
dc.subject.otherHumans
dc.subject.otherMice
dc.subject.otherCOS Cells
dc.subject.otherNIH 3T3 Cells
dc.subject.otherCell Nucleus
dc.subject.otherMelanoma
dc.subject.otherBreast Neoplasms
dc.subject.otherCell Transformation, Neoplastic
dc.subject.otherp38 Mitogen-Activated Protein Kinases
dc.subject.otherT-Box Domain Proteins
dc.subject.otherUltraviolet Rays
dc.subject.otherCell Aging
dc.subject.otherActive Transport, Cell Nucleus
dc.subject.otherPhosphorylation
dc.subject.otherMAP Kinase Signaling System
dc.subject.otherUp-Regulation
dc.subject.otherCyclin-Dependent Kinase Inhibitor p21
dc.subject.otherCyclin-Dependent Kinase Inhibitor p16
dc.subject.otherCell Line, Tumor
dc.subject.otherMutagenesis, Site-Directed
dc.subject.otherCell Cycle
dc.titleUV-mediated Regulation of the anti-senescence factor Tbx2
dc.typeJournal Article
uct.type.publicationResearch
uct.type.resourceJournal Article
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