Abstract
BackgroundTBX3, a member of the T-box family of transcription factors, is essential in development and has emerged as an important player in the oncogenic process. TBX3 is overexpressed in several cancers and has been shown to contribute directly to tumour formation, migration and invasion. However, little is known about the molecular basis for its role in development and oncogenesis because there is a paucity of information regarding its target genes. The cyclin-dependent kinase inhibitor p21WAF1 plays a pivotal role in a myriad of processes including cell cycle arrest, senescence and apoptosis and here we provide a detailed mechanism to show that it is a direct and biologically relevant target of TBX3.ResultsUsing a combination of luciferase reporter gene assays and in vitro and in vivo binding assays we show that TBX3 directly represses the p21WAF1 promoter by binding a T-element close to its initiator. Furthermore, we show that the TBX3 DNA binding domain is required for the transcriptional repression of p21WAF1 and that pseudo-phosphorylation of a serine proline motif (S190) located within this domain may play an important role in regulating this ability. Importantly, we demonstrate using knockdown and overexpression experiments that p21WAF1 repression by TBX3 is biologically significant and required for TBX3-induced cell proliferation of chondrosarcoma cells.ConclusionsResults from this study provide a detailed mechanism of how TBX3 transcriptionally represses p21WAF1 which adds to our understanding of how it may contribute to oncogenesis.
Highlights
TBX3, a member of the T-box family of transcription factors, is essential in development and has emerged as an important player in the oncogenic process
We used the ATDC5 and SW1353 chondrosarcoma cell lines because we recently reported that TBX3 promotes their proliferation and we showed that this was accompanied by a decrease in p21 protein levels [13]
Comparable protein expression was observed for all three constructs tested in the luciferase assays. This data suggest that TBX3 regulates p21 by directly binding to it and that the dominant repression domain R1 is important for p21 repression
Summary
TBX3, a member of the T-box family of transcription factors, is essential in development and has emerged as an important player in the oncogenic process. The cyclin-dependent kinase inhibitor p21WAF1 plays a pivotal role in a myriad of processes including cell cycle arrest, senescence and apoptosis and here we provide a detailed mechanism to show that it is a direct and biologically relevant target of TBX3. TBX3 is able to bypass senescence and/or evade apoptosis by transcriptionally repressing p14ARF/p19ARF via a variant T-element [8, 24,25,26] This has led to the speculation that TBX3 may bind this degenerate T-element with low affinity and that it may impact on the above processes by targeting the p19ARFMdm2-p53-p21WAF pathway at multiple points for example by repressing p19ARF, p53 and p21WAF (hereafter referred to as p21) and/or activating Mdm2 [27]. The mechanism by which TBX3 regulates p21 has yet to be elucidated and whether this regulation is biological relevant still needs to be confirmed
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