TBX3, a downstream target of TGF-β1, inhibits mesangial cell apoptosis
Abstract
Chronic kidney disease (CKD) is an increasingly common condition characterized by progressive loss of functional nephrons leading to renal failure. TGF-β1-induced mesangial cell (MC) phenotype alterations have been linked to the genesis of CKD. Here we show that TGF-β1 regulates TBX3 gene expression in MC. This gene encodes for two main isoforms, TBX3.1 and TBX3+2α. TBX3.1 has been implicated in cell immortalization, proliferation and apoptosis by inhibiting p14(ARF)-Mdm2-p53 pathway, while TBX3+2α role has not been defined. We demonstrated that TBX3 overexpression abrogated MC apoptosis induced by serum deprivation. Moreover, we observed an enhancement in TBX3 protein expression both in glomerular and tubular regions in the model of 5/6 nephrectomy, temporally related to increased expression of TGF-β1, type IV collagen and fibronectin. Our results indicate that TBX3 acts as an anti-apoptotic factor in MC in vitro and may be involved in the mechanism by which TGF-β1 induces glomerulosclerosis and tubular fibrosis during the progression of nephropathies.
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TBX3 functions primarily as a transcriptional repressor and initial reports suggested that it can promote proliferation by repressing the cell cycle regulators p14/p19ARF and p21.
“TBX3 functions primarily as a transcriptional repressor and initial reports suggested that it can promote proliferation by repressing the cell cycle regulators p14/p19ARF and p21 [60–62].”
From The oncoprotein TBX3 is controlling severity in experimental arthritis (2019) · cites this paper as [62]
Cites
The BCL-2 protein family: opposing activities that mediate cell death
Youle, R. J., & Strasser, A. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2308 · Cited by 4,704 · see citing works
Role of duplicate genes in genetic robustness against null mutations
Gu, Z., Steinmetz, L. M., Gu, X., Scharfe, C., Davis, R. W., & Li, W.-H. (2003) · Nature · doi:10.1038/nature01198 · Cited by 889 · see citing works
A parallel circuit of LIF signalling pathways maintains pluripotency of mouse ES cells
Niwa, H., Ogawa, K., Shimosato, D., & Adachi, K. (2009) · Nature · doi:10.1038/nature08113 · Cited by 872 · see citing works
Positional effects of short interfering RNAs targeting the human coagulation trigger Tissue Factor
Holen, T. (2002) · Nucleic Acids Research · doi:10.1093/nar/30.8.1757 · Cited by 706 · see citing works
Extracellular Matrix Metabolism in Diabetic Nephropathy
Mason, R. M., & Wahab, N. A. (2003) · Journal of the American Society of Nephrology · doi:10.1097/01.asn.0000065640.77499.d7 · Cited by 653 · see citing works
Apoptosis in podocytes induced by TGF-β and Smad7
Schiffer, M., Bitzer, M., Roberts, I. S. D., Kopp, J. B., ten Dijke, P., Mundel, P. H., & Böttinger, E. P. (2001) · Journal of Clinical Investigation · doi:10.1172/jci200112367 · Cited by 597 · see citing works
Pathways to nephron loss starting from glomerular diseases—Insights from animal models
Kriz, W., & LeHir, M. (2005) · Kidney International · doi:10.1111/j.1523-1755.2005.67097.x · Cited by 462 · see citing works
Diaeresis]ndorff, D. S., & Banas, B. (2009) · Journal of the American Society of Nephrology · doi:10.1681/asn.2008050549 · Cited by 408 · see citing works
TGF-β in kidney fibrosis: A target for gene therapy
Border, W. A., & Noble, N. A. (1997) · Kidney International · doi:10.1038/ki.1997.190 · Cited by 378 · see citing works
Davenport, T. G., Jerome-Majewska, L. A., & Papaioannou, V. E. (2003) · Development · doi:10.1242/dev.00431 · Cited by 295 · see citing works
Role of TGF-β in chronic kidney disease: an integration of tubular, glomerular and vascular effects
López-Hernández, F. J., & López-Novoa, J. M. (2011) · Cell and Tissue Research · doi:10.1007/s00441-011-1275-6 · Cited by 276 · see citing works
Apoptosis in glomerular sclerosis
Sugiyama, H., Kashihara, N., Makino, H., Yamasaki, Y., & Ota, Z. (1996) · Kidney International · doi:10.1038/ki.1996.14 · Cited by 256 · see citing works
Johnson, R. J., Floege, J., Yoshimura, A., Iida, H., Couser, W. G., & Alpers, C. E. (1992) · Journal of the American Society of Nephrology · doi:10.1681/asn.v210s190 · Cited by 222 · see citing works
Glomerular Mesangial Cells: Electrophysiology and Regulation of Contraction
Stockand, J. D., & Sansom, S. C. (1998) · Physiological Reviews · doi:10.1152/physrev.1998.78.3.723 · Cited by 220 · see citing works
Abboud, H. E. (2012) · Experimental Cell Research · doi:10.1016/j.yexcr.2012.02.025 · Cited by 215 · see citing works
Luo, K. Q., & Chang, D. C. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.04.027 · Cited by 194 · see citing works
Role of the Akt/FoxO3a Pathway in TGF-β1–Mediated Mesangial Cell Dysfunction
Kato, M. V., Yuan, H., Xu, Z., Lanting, L. L., Li, S., Wang, M., Hu, M. C. ‐., Reddy, M. A., & Natarajan, R. D. (2006) · Journal of the American Society of Nephrology · doi:10.1681/asn.2006070754 · Cited by 174 · see citing works
Lingbeek, M. E., Jacobs, J. J. L., & van Lohuizen, M. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m200403200 · Cited by 160 · see citing works
Renard, C.-A., Labalette, C., Armengol, C., Cougot, D., Wei, Y., Cairo, S., Pineau, P., Neuveut, C., de Reyniès, A., Dejean, A., et al. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-2344 · Cited by 157 · see citing works
Tbx3 Represses E-Cadherin Expression and Enhances Melanoma Invasiveness
Rodriguez, M., Aladowicz, E., Lanfrancone, L., & Goding, C. R. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-0301 · Cited by 157 · see citing works
Brummelkamp, T. R., Kortlever, R. M., Lingbeek, M., Trettel, F., MacDonald, M. E., van Lohuizen, M., & Bernards, R. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m110492200 · Cited by 154 · see citing works
Wang, D., Dai, C., Li, Y., & Liu, Y. (2011) · Kidney International · doi:10.1038/ki.2011.255 · Cited by 150 · see citing works
Tbx2 and Tbx3 induce atrioventricular myocardial development and endocardial cushion formation
Singh, R., Hoogaars, W. M. H., Barnett, P., Grieskamp, T., Rana, M. S., Buermans, H. P. J., Farin, H. F., Petry, M., Heallen, T. R., Martin, J. F., et al. (2011) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-011-0884-2 · Cited by 145 · see citing works
Suzuki, A., Sekiya, S., Büscher, D., Izpisúa Belmonte, J. C., & Taniguchi, H. (2008) · Development · doi:10.1242/dev.016634 · Cited by 136 · see citing works
Fan, W., Huang, X., Chen, C., Gray, J., & Huang, T. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-0615 · Cited by 136 · see citing works
TGF-β1 Protects against Mesangial Cell Apoptosis via Induction of Autophagy
Ding, Y., Kim, J. K., Kim, S. I., Na, H.-J., Jun, S. Y., Lee, S., & Choi, M. E. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.093724 · Cited by 130 · see citing works
Cellular apoptosis and proliferation in experimental renal fibrosis
Thomas, G. L. (1998) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/13.9.2216 · Cited by 125 · see citing works
Baricos, W. H., Cortez, S. L., deBoisblanc, M. W., & XIN, S. (1999) · Journal of the American Society of Nephrology · doi:10.1681/asn.v104790 · Cited by 122 · see citing works
Carlson, H. (2001) · Human Molecular Genetics · doi:10.1093/hmg/10.21.2403 · Cited by 108 · see citing works
Role of Smad4 on TGF-β–induced extracellular matrix stimulation in mesangial cells
Tsuchida, K., Zhu, Y., Siva, S., Dunn, S., & Sharma, K. (2003) · Kidney International · doi:10.1046/j.1523-1755.2003.00009.x · Cited by 104 · see citing works
Carlson, H., Ota, S., Song, Y., Chen, Y., & Hurlin, P. J. (2002) · Oncogene · doi:10.1038/sj.onc.1205476 · Cited by 102 · see citing works
The Role of Tbx2 and Tbx3 in Mammary Development and Tumorigenesis
Rowley, M., Grothey, E., & Couch, F. J. (2004) · Journal of Mammary Gland Biology and Neoplasia · doi:10.1023/b:jomg.0000037156.64331.3f · Cited by 97 · see citing works
Role of Duplicate Genes in Robustness against Deleterious Human Mutations
Hsiao, T., & Vitkup, D. (2008) · PLoS Genetics · doi:10.1371/journal.pgen.1000014 · Cited by 96 · see citing works
Douthwaite, J. A., Johnson, T. S., Haylor, J., Watson, P. F., & Nahas, A. M. E. (1999) · Journal of the American Society of Nephrology · doi:10.1681/asn.v10102109 · Cited by 84 · see citing works
Regulation of human mesangial cell collagen expression by transforming growth factor-β1
Poncelet, A.-C., & Schnaper, H. W. (1998) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.1998.275.3.f458 · Cited by 80 · see citing works
Lu, R., Yang, A., & Jin, Y. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.202150 · Cited by 80 · see citing works
Floege, J., Topley, N., HOPPE, I., Barrett, T. B., & Resch, K. (1991) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.1991.tb05819.x · Cited by 80 · see citing works
Monkawa, T., Hiromura, K., Wolf, G., & Shankland, S. J. (2002) · Journal of the American Society of Nephrology · doi:10.1097/01.asn.0000013162.29833.45 · Cited by 77 · see citing works
Wersto, R. P., Rosenthal, E. R., Seth, P. K., Eissa, N. T., & Donahue, R. E. (1998) · Journal of Virology · doi:10.1128/jvi.72.12.9491-9502.1998 · Cited by 76 · see citing works
Apoptosis and extracellular matrix–cell interactions in kidney disease
Makino, H., Sugiyama, H., & Kashihara, N. (2000) · Kidney International · doi:10.1046/j.1523-1755.2000.07711.x · Cited by 75 · see citing works
Yano, T., Yamazaki, Y., Adachi, M., Okawa, K., Fort, P., Uji, M., Tsukita, S., & Tsukita, S. (2011) · The Journal of Cell Biology · doi:10.1083/jcb.201009100 · Cited by 75 · see citing works
Teramoto, S., Johnson, L. G., Huang, W., Leigh, M. W., & Boucher, R. C. (1995) · Human Gene Therapy · doi:10.1089/hum.1995.6.8-1045 · Cited by 74 · see citing works
Wang, B., Lindley, L. E., Fernández-Vega, V., Rieger, M. E., Sims, A. H., & Briegel, K. J. (2012) · PLoS ONE · doi:10.1371/journal.pone.0041355 · Cited by 64 · see citing works
TBX3 and its splice variant TBX3 + exon 2a are functionally similar
Hoogaars, W. M. H., Barnett, P., Rodríguez, M., Clout, D. E. W., Moorman, A. F. M., Goding, C. R., & Christoffels, V. M. (2008) · Pigment Cell & Melanoma Research · doi:10.1111/j.1755-148x.2008.00461.x · Cited by 62 · see citing works
Mesangial cells in the pathogenesis of progressive glomerular disease in animal models
Floege, J., Johnson, R. J., & Couser, W. G. (1992) · Journal of Molecular Medicine · doi:10.1007/bf00180756 · Cited by 62 · see citing works
Cell-matrix interactions in the glomerular mesangium
Rupprecht, H., Schöcklmann, H. O., & Sterzel, R. B. (1996) · Kidney International · doi:10.1038/ki.1996.228 · Cited by 59 · see citing works
TBX2 and TBX3: The special value for anticancer drug targets
Lu, J., Li, X.-P., Dong, Q., Kung, H.-F., & He, M.-L. (2010) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2010.07.001 · Cited by 57 · see citing works
The oncogenic TBX3 is a downstream target and mediator of the TGF-β1 signaling pathway
Li, J., Weinberg, M. S., Zerbini, L., & Prince, S. (2013) · Molecular Biology of the Cell · doi:10.1091/mbc.e13-05-0273 · Cited by 56 · see citing works
ITO, A., ASAMOTO, M., HOKAIWADO, N., TAKAHASHI, S., & SHIRAI, T. (2005) · Cancer Letters · doi:10.1016/j.canlet.2004.07.051 · Cited by 55 · see citing works
Lee, H. S., & Song, C. Y. (2009) · PubMed · doi:10.14670/hh-24.901 · Cited by 53 · see citing works
Multiple interacting domains contribute to p14ARF mediated inhibition of MDM2
Clark, P. A., Llanos, S., & Peters, G. G. (2002) · Oncogene · doi:10.1038/sj.onc.1205558 · Cited by 39 · see citing works
T-box genes and the formation of vertebrate forelimb- and hindlimb specific pattern
Simon, H. (1999) · Cell and Tissue Research · doi:10.1007/s004410051266 · Cited by 38 · see citing works
Humtsoe, J. O., Koya, E., Pham, E., Aramoto, T., Zuo, J., Ishikawa, T., & Kramer, R. H. (2011) · Experimental Cell Research · doi:10.1016/j.yexcr.2011.11.011 · Cited by 36 · see citing works
Patel, P., Varghese, E., Ding, G., Fan, S., Kapasi, A. A., Reddy, K., Franki, N., Nahar, N., & Singhal, P. C. (2000) · Journal of Investigative Medicine · doi:10.1177/108155890004800610 · Cited by 30 · see citing works
Sox4 mediates Tbx3 transcriptional regulation of the gap junction protein Cx43
Boogerd, C. J. J., Wong, L. Y. E., van den Boogaard, M., Bakker, M. L., Tessadori, F., Bakkers, J., Hoen, P. A. C. ’., Moorman, A. F. M., Christoffels, V. M., & Barnett, P. (2011) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-011-0693-7 · Cited by 30 · see citing works
Mené, P. (2001) · PubMed · Cited by 29 · see citing works
Alternative splicing of T-box transcription factor genes
DeBenedittis, P., & Jiao, K. (2011) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2011.08.010 · Cited by 20 · see citing works
Dynamic expression of Tbx2 and Tbx3 in developing mouse pancreas
Begum, S., & Papaioannou, V. E. (2011) · Gene Expression Patterns · doi:10.1016/j.gep.2011.08.003 · Cited by 12 · see citing works
Flagged first, then by citations
2 of the 60 references couldn’t be matched to a known paper.
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Sorted by citations
Guidelines and definitions for research on epithelial-mesenchymal transition
Yang, J., Antin, P., Berx, G., Blanpain, C., Brabletz, T., Bronner, M., Campbell, K., Cano, A., Casanova, J., Christofori, G., et al. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0237-9 · Cited by 2,226 · see citing works
The roles and regulation of TBX3 in development and disease
Khan, S. F., Damerell, V., Omar, R., Du Toit, M., Khan, M., Maranyane, H. M., Mlaza, M., Bleloch, J., Bellis, C., Sahm, B. D. B., et al. (2020) · Gene · doi:10.1016/j.gene.2019.144223 · Cited by 99 · see citing works
“On the other hand, the ectopic overexpression of TBX3 or TBX3+2a in human mesangial cells inhibited apoptosis (Wensing and Campos, 2014).”
BackgroundThe T-Box transcription factor 3 in development and cancer
Willmer, T., Cooper, A., Peres, J., Omar, R., & Prince, S. (2017) · BioScience Trends · doi:10.5582/bst.2017.01043 · Cited by 44 · see citing works
Amaral, L. S. D. B., Silva, F. A., Correia, V. B., Andrade, C. E., Dutra, B. A., Oliveira, M. V., de Magalhães, A. C. M., Volpini, R. A., Seguro, A. C., Coimbra, T. M., et al. (2015) · Experimental Biology and Medicine · doi:10.1177/1535370215609696 · Cited by 39 · see citing works
The oncoprotein TBX3 is controlling severity in experimental arthritis
Sardar, S., Kerr, A., Vaartjes, D., Moltved, E. R., Karosiene, E., Gupta, R., & Andersson, Å. (2019) · Arthritis Research & Therapy · doi:10.1186/s13075-018-1797-3 · Cited by 13 · see citing works
“Tbx3 (+) Expressed in colon, lung, heart, liver, adrenal gland and spleen Controls cell proliferation and differentiation [37, 60, 62]; enhances tumor invasiveness [18]; regulates gene splicing [68]; modulates number of cell signaling pathways involved in the development of limb, mammary gland, and heart [18]; regulat…”
BackgroundBcl-2 Overexpression Induces Neurite Outgrowth via the Bmp4/Tbx3/NeuroD1 Cascade in H19-7 Cells
Lee, Y. Y., Choi, H. J., Lee, S. Y., Park, S., Kang, M.-J., Han, J., & Han, J. (2019) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-019-00732-1 · Cited by 11 · see citing works
T-box 3 overexpression is associated with poor prognosis of non-small cell lung cancer
Wu, Y., Jiang, F., Hu, W., & Zhang, Y. (2017) · Oncology Letters · doi:10.3892/ol.2017.5855 · Cited by 9 · see citing works
Huang, Y., Zhu, H., Ji, X., Chen, Y., Zhang, Y., Huang, R., Xie, J., & Dong, P. (2019) · Oncology Letters · doi:10.3892/ol.2019.11089 · Cited by 9 · see citing works
TGF-β1 alleviates HgCl2 induced apoptosis via P38 MAPK signaling pathway in human trophoblast cells
Zhou, G., Li, Z., Sun, S., Fang, Y., & Wei, Z. (2019) · Toxicology in Vitro · doi:10.1016/j.tiv.2019.104626 · Cited by 8 · see citing works
Permatasari, H. K., Bdira, S. B., Moon, M., Amalia, N., Sulistomo, H. W., Riawan, W., Choi, J., Chung, S., Park, M. N., Seo, B.-K., et al. (2023) · Journal of Agriculture and Food Research · doi:10.1016/j.jafr.2023.100796 · Cited by 5 · see citing works
Jia, H., Miyoshi, M., Li, X., Furukawa, K., Otani, L., Shirahige, K., Miura, F., Ito, T., & Kato, H. (2023) · Nutrients · doi:10.3390/nu15183957 · Cited by 4 · see citing works
Role of T-box transcription factor 3 in gastric cancers
Asano, N., Imatani, A., Takeuchi, A., Saito, M., Jin, X., Hatta, W., Uno, K., Koike, T., & Masamune, A. (2023) · World Journal of Gastrointestinal Pathophysiology · doi:10.4291/wjgp.v14.i2.12 · Cited by 2 · see citing works
GATA6 and TBX3 gene expressions analysis of indirect inguinal hernia sacs in children
Kizilkaya, O., Köprülü, M. S., Gürkan, H., & İnan, M. (2025) · Pediatric Surgery International · doi:10.1007/s00383-025-06065-z · Cited by 1 · see citing works
Reilly, M. L. (2018) · theses.fr (ABES) · doi:10.70675/dc69ccc1zaa2fz4147z8d1bzf306462e1009
- Authors
- Wensing, L. A., & Campos, A. H.
- Affiliations
- Universidade de São Paulo (BR)
- Hospital Israelita Albert Einstein (BR)
- Venue
- Experimental Cell Research
- Publisher
- Elsevier BV
- Published
- 2014-11
- Volume
- 328
- Issue
- 2
- Pages
- 340-350
- ISSN
- 0014-4827 (ISSN-L)
- OpenAlex
- W2021304773
- Cited by
- 15
- References
- 60
- Citations by year
- 2025: 1 · 2023: 3 · 2020: 1 · 2019: 5 · 2018: 2 · 2017: 2 · 2015: 1
- FWCI
- 0.41
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Experimental Cell Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fundação de Amparo a Pesquisa do Estado de São Paulo (#07/02864-1)
- SBIB Albert Einstein
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Health Sciences › Medicine › Nephrology › Renal Diseases and Glomerulopathies
- Keywords
- TBX3, TGF-β1, mesangial cells, apoptosis, chronic kidney disease, glomerulosclerosis, tubular fibrosis, 5/6 nephrectomy, serum deprivation, type IV collagen, fibronectin, anti-apoptotic factors
- MeSH terms
- Cells, Cultured, Fibronectins, Fibrosis, Humans, Gene Expression, Apoptosis, Protein Isoforms, T-Box Domain Proteins, Collagen Type IV, Cell Proliferation, Mesangial Cells, Transforming Growth Factor beta1
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