Senescence bypass screen identifies TBX2, which represses Cdkn2a (p19ARF) and is amplified in a subset of human breast cancers

Abstract

To identify new immortalizing genes with potential roles in tumorigenesis, we performed a genetic screen aimed to bypass the rapid and tight senescence arrest of primary fibroblasts deficient for the oncogene Bmi1. We identified the T-box member TBX2 as a potent immortalizing gene that acts by downregulating Cdkn2a (p19(ARF)). TBX2 represses the Cdkn2a (p19(ARF)) promoter and attenuates E2F1, Myc or HRAS-mediated induction of Cdkn2a (p19(ARF)). We found TBX2 to be amplified in a subset of primary human breast cancers, indicating that it might contribute to breast cancer development.

Ectopic Tbx2 expression results in polyploidy and cisplatin resistance

“…It is therefore possible that altered Tbx2 protein levels affect chromosome segregation as well as negatively regulating normal surveillance mechanisms that would otherwise eliminate polyploid cells. We speculate that Tbx2 may be doing this, through regulating key cell cycle regulators especially since Tbx2 has been shown to interact directly with and repress the cell cycle regulators p19 ARF (Jacobs et al, 2000;Brummelkamp et al, 2002) and p21 (Prince et al, 2004). We show that the changes observed in our Tbx2-expressing cells are not associated with alterations in p53, p21 or cyclin B protein levels but with increased levels of p14 ARF .…”

“…In addition, T-box factors have been implicated in cell cycle regulation and in the genesis of cancer. Both Tbx2 and Tbx3, for example, can prevent senescence in mouse embryonic fibroblasts and ST.Hdh Q111 striatal cells through a mechanism involving their ability to repress the cyclin-dependent kinase inhibitors p19 ARF (Jacobs et al, 2000;Carlson et al, 2001;Brummelkamp et al, 2002) and p21 WAF1/CIP1/SDII (referred to as p21) (Prince et al, 2004). Ectopic expression of Tbx3 together with oncogenic Ras or Myc in embryonic mouse fibroblasts leads to cellular transformation and suppression of apoptosis (Carlson et al, 2002).…”

Genomic profiling of malignant melanoma using tiling-resolution arrayCGH

“…An interesting adjacent gene on 17q23.2 is TBX2, highly expressed in melanoma cells where it plays an important role in maintaining proliferation and suppression of senescence (Vance et al, 2005), possibly by downregulation of p21CIP1 and CDKN2A/p19ARF (Jacobs et al, 2000;Vance et al, 2005). TBX2 is one of the known targets for MITF in melanocytes, and a strong candidate melanoma oncogene (Carreira et al, 2000).…”

Activation and activities of the p53 tumour suppressor protein

“…The importance of the ARF/p53 pathway is illustrated in mice, where deletion of ARF results in tumour development (Kamijo et al, 1997). Although mutations specific to ARF are rarely found in human tumours, loss of ARF expression resulting from methylation of the ARF promoter (Esteller, 2000), or overexpression of transcriptional repressors of ARF such as Twist (Maestro et al, 1999), Bmi-1 (Jacobs et al, 1999) or TBX2 (Jacobs et al, 2000) is associated with human cancer development.…”