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

Abstract

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.

The T-Box transcription factor 3 in development and cancer

“…increased levels of TBX3 in S-phase were shown to occur transcriptionally through activation by c-Myc at E-box motifs located at -1210 and -701 bps and posttranslationally by cyclin A-CDK2 phosphorylation (51). Together these results suggest that TBX3 functions as a pro-proliferative factor, in part, by promoting transition into G2/M.…”

Overexpression of TBX3 transcription factor as a potential diagnostic marker for breast cancer

“…Significantly, the current study provides more statistical analysis to show the importance of TBX3 as a marker of breast cancer cells. Another recent study found that TBX3 protein has different levels and localizations in the different stages of cell cycle (1). The study showed that TBX3 levels increases during G1 and peaks in S-phase.…”

“…Breast cancer is the most common malignancy worldwide and it is estimated that one out of eight women will develop breast cancer in their life time (1,2). Unfortunately, in spite of the enormous efforts invested to treat breast cancer there has been limited success because many patients still diagnosed too late and several types of breast tumours develop resistance to the current chemotherapies (3,4).…”

The T-box transcription factor 3 is a promising biomarker and a key regulator of the oncogenic phenotype of a diverse range of sarcoma subtypes

“…41 Interestingly, TBX3 is positively regulated by AKT, Wnt/β-catenin and c-Myc in melanoma, liver cancer and chondrosarcomas, respectively, and it directly represses PTEN to promote head and neck carcinomas. 13, 42, 43 It will thus be worth investigating whether these signalling networks regulate TBX3-induced sarcoma cell migration.…”