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

Prolonged culturing of rodent cells in vitro activates p19 super(ARF) (named p14 super(ARF) in man), resulting in a p53-dependent proliferation arrest known as senescence. The p19 super(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 Ulnar-Mammary Syndrome. We have shown that TBX-3 potently represses expression of both mouse p19 super(ARF) and human p14 super(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 super(ARF) and human p14 super(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 super(ARF).