The T-box transcription factor TBX3 drives proliferation by direct repression of the p21 WAF1 cyclin-dependent kinase in
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Willmer et al. Cell Div (2016) 11:6 DOI 10.1186/s13008-016-0019-0
Open Access
RESEARCH
The T‑box transcription factor TBX3 drives proliferation by direct repression of the p21WAF1 cyclin‑dependent kinase inhibitor Tarryn Willmer†, Shannagh Hare†, Jade Peres and Sharon Prince*
Abstract Background: 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. 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. Results: Using 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. Conclusions: Results 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. Keywords: TBX3, Transcription factor, p21WAF1, Cancer Background Members of the T-box transcription factor family play crucial roles in embryonic development [1–4] and there is overwhelming evidence to show that they impact on several cancers by functioning as tumour suppressors and/or tumour promoters [5–13]. For example, TBX3 is critical for the formation of, amongst other structures, the heart, limbs and mammary glands and haploinsufficiency of the human TBX3 gene results in ulnar-mammary syndrome which is characterized by hypoplasia of these structures [14–16]. On the other hand, the *Correspondence: [email protected] † Tarryn Willmer and Shannagh Hare contributed equally to this work Division of Cell Biology, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town 7925, South Africa
overexpression of TBX3 is a feature of a wide range of cancers and it is a key driver of several oncogenic processes including proliferation, migration and invasion [9, 11, 12, 16–20]. There are also a few studies that have described a tumour suppressor role for TBX3 in cervical, uterine and bladder tumours, glioblastomas and fibrosarcoma
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