TBX-3, the Gene Mutated in Ulnar-Mammary Syndrome, Is a Negative Regulator of p19 and Inhibits Senescence

Abstract

Prolonged culturing of rodent cells in vitro activates p19ARF (named p14 ARF in man), resulting in a p53-dependent proliferation arrest known as senescence. The p19 ARF -Mdm2-p53 pathway also serves to protect primary cells against oncogenic transformation. We have used a genetic screen in mouse neuronal cells, conditionally immortalized by a temperature-sensitive mutant of SV40 large T antigen, to identify genes that allow bypass of senescence. Using retroviral cDNA expression libraries, we have identified TBX-3 as a potent inhibitor of senescence. TBX-3 is a T-box gene, which is found mutated in the human developmental disorder UlnarMammary Syndrome. We have shown that TBX-3 potently represses expression of both mouse p19 ARF and human p14 ARF . We have also shown here that point mutants of TBX-3, which are found in Ulnar-Mammary Syndrome, have lost the ability to inhibit senescence and fail to repress mouse p19 ARF and human p14 ARF expression. These data suggest that the hypoproliferative features of this genetic disorder may be caused, at least in part, by deregulated expression of p14 ARF .

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).…”

Increased expression of cSHMT, Tbx3 and utrophin in plasma of ovarian and breast cancer patients

“…15 Tbx3 has been described as a potent inhibitor of senescence of neuronal cells and embryonal fibroblasts. 18 Utrophin has been described first as a protein involved in development of neuromuscular junctions. However, utrophin detection in a variety of cells has indicated its role in organization of connections between cytoskeleton and transmembrane proteins.…”

Myc pathways provoking cell suicide and cancer

“…Thus, Myc must work through the agency of other transcription factors or signaling proteins that regulate Arf transcription. Indeed some likely culprits have been identified, including the transcription factors Bmi-1, Twist, Tbx2 and Tbx3, all of which repress Arf transcription and block Mycinduced apoptosis (Jacobs et al, 1999a(Jacobs et al, , 2000Maestro et al, 1999;Brummelkamp et al, 2002;Carlson et al, 2002;Lingbeek et al, 2002). Furthermore, reductions in Bmi-1 impair Myc-induced tumorigenesis through augmenting an Arf-dependent apoptotic response (Jacobs et al, 1999a).…”