UV-mediated Regulation of the Anti-senescence Factor Tbx2

Abrahams, Amaal; Mowla, Shaheen; Parker, M. Iqbal; Goding, Colin R.; Prince, Sharon

doi:10.1074/jbc.m705651200

Cited by 38 publications

(44 citation statements)

References 47 publications

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“…This possibility is consistent with the nuclear localization of TBX2 being regulated by phosphorylation in response to cellular stress. 43 Given the importance of cyclin A-CDK2 in S-phase, these results provide additional support that TBX3 must play an important role during this stage of the cell cycle. Cyclin A-CDK2 promotes S-phase progression by either directly phosphorylating substrates such as Cdh1, Rb, p21 and p27 or indirectly by phosphorylating substrates that are able to regulate these factors.…”

Section: Discussionmentioning

confidence: 64%

The T-Box factor TBX3 is important in S-phase and is regulated by c-Myc and cyclin A-CDK2

et al. 2015

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The transcription factor, TBX3, is critical for the formation of, among other structures, the heart, limbs and mammary glands and haploinsufficiency of the human TBX3 gene result in ulnar-mammary syndrome which is characterized by hypoplasia of these structures. On the other hand, the overexpression of TBX3 is a feature of a wide range of cancers and it has been implicated in several aspects of the oncogenic process. This includes its ability to function as an immortalizing gene and to promote proliferation through actively repressing negative cell cycle regulators. Together this suggests that TBX3 levels may need to be tightly regulated during the cell cycle. Here we demonstrate that this is indeed the case and that TBX3 mRNA and protein levels peak at S-phase and that the TBX3 protein is predominantly localized to the nucleus of S-phase cells. The increased levels of TBX3 in S-phase are shown to occur transcriptionally through activation by c-Myc at E-box motifs located at ¡1210 and ¡701 bps and post-translationally by cyclin A-CDK2 phosphorylation. Importantly, when TBX3 is depleted by shRNA the cells accumulate in S-phase. These results suggest that TBX3 is required for cells to transit through S-phase and that this function may be linked to its role as a proproliferative factor.

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Section: Discussionmentioning

confidence: 64%

The T-Box factor TBX3 is important in S-phase and is regulated by c-Myc and cyclin A-CDK2

et al. 2015

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“…Tbx5 localizes to both the nucleus and cytoplasm in tissue sections from developing chick hearts (30) and deletion of the TBX5 NLS, at amino acids 325-327 within its C-terminal region, is sufficient to prevent nuclear localization of the protein (27). TBX2 is localized to both the cytoplasm and nucleus but upon UVC irradiation, phosphorylation of TBX2 by the p38 mitogen-activated protein (MAP) kinase lead to the exclusive nuclear localization of the protein (31). Interestingly, in Caenorhabditis elegans, tbx-2 is involved in olfactory adaptation and is expressed in AWB, AWC, ASJ, and many pharyngeal neurons where the protein is mostly localized to the cytoplasm, suggesting that nuclear translocation may regulate its activity (32).…”

Section: The T-box Gene Familymentioning

confidence: 99%

The T‐box transcription factor Tbx2: Its role in development and possible implication in cancer

2009

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SummaryTbx2 is a member of the T-box family of transcription factors that are crucial in embryonic development. Recent studies suggest that T-box factors may also play a role in controlling cell cycle progression and in the genesis of cancer. Tbx2 has been implicated in several developmental processes such as coordinating cell fate, patterning and morphogenesis of a wide range of tissues and organs including limbs, kidneys, lungs, mammary glands, heart, and craniofacial structures. Importantly, Tbx2 is overexpressed in several cancers including melanoma, small cell lung carcinoma, breast, pancreatic, liver, and bladder cancers and can suppress senescence, a cellular process, which serves as a barrier to cancer development. This review presents a state of the art overview of the role and regulation of Tbx2 in early embryonic development and in cancer.

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“…31 Reactions were performed using the primers for human TBX3 (QT00022484; Qiagen, Valencia, CA), E-cadherin (1863250; Integrated DNA Technologies), and GAPDH (forward 5′-GAAGGCT GGGGCTCATTT-3′; reverse 5′-CAGGAGGCATTGCTGA TGAT-3′).…”

Section: Quantitative Real-time Pcr (Qrt-pcr)mentioning

confidence: 99%

“…Interestingly, the p38 kinase, which we previously showed upregulates TBX2 levels in response to DNA damage, 31 was reported to influence cell proliferation similarly with no effect on motility in mouse melanoma cells treated with hepatocyte growth factor/scatter factor. The finding that reduced TBX2 levels did not affect the migration rate of cancer cells is interesting in light of our data obtained for its closely related family member TBX3.…”

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confidence: 99%

The Highly Homologous T-Box Transcription Factors, TBX2 and TBX3, Have Distinct Roles in the Oncogenic Process

et al. 2010

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The T-box transcription factors TBX2 and TBX3 are overexpressed in several cancers and are able to bypass senescence by repressing ARF and p21 WAF1/CIP1/SDII . Although these studies suggest that they may both contribute to the oncogenic process by repressing common targets, whether they have redundant or distinct roles in cancers where they are both overexpressed remains to be elucidated. Importantly, when Tbx2 function is inhibited in melanoma cells lacking Tbx3, the cells senesce, but whether this is possible in melanoma cells overexpressing both proteins is not known. An understanding of this issue may have important implications for the design of an effective pro-senescence therapy. In this study, the authors used a sh-RNA approach to knock down TBX2 and TBX3 individually in 2 human melanoma cell lines that overexpress both these factors and then examined their specific involvement in the oncogenic process. They demonstrate, using in vitro and in vivo cell proliferation, as well as colony-and tumor-forming ability and cell motility assays, that TBX2 and TBX3 have distinct roles in melanoma progression. In the tested lines, although TBX2 could promote proliferation and transformation and was required by primary melanoma cells for immortality, TBX3 was required for tumor formation and cell migration. These findings were reproducible in a human breast cancer cell line, which confirms that TBX2 and TBX3, although highly homologous, do not have redundant roles in the transformation process of cancers where they are both overexpressed. These results have important implications for the development of new cancer treatments and in particular for melanoma, which is a highly aggressive and intractable cancer.

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UV-mediated Regulation of the Anti-senescence Factor Tbx2

Cited by 38 publications

References 47 publications

The T-Box factor TBX3 is important in S-phase and is regulated by c-Myc and cyclin A-CDK2

The T-Box factor TBX3 is important in S-phase and is regulated by c-Myc and cyclin A-CDK2

The T‐box transcription factor Tbx2: Its role in development and possible implication in cancer

The Highly Homologous T-Box Transcription Factors, TBX2 and TBX3, Have Distinct Roles in the Oncogenic Process

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