TBX-3, the gene mutated in Ulnar-Mammary Syndrome, is a negative regulator of p19ARF and inhibits senescence.
Prolonged culturing of rodent cells in vitro activates p19(ARF) (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 Ulnar-Mammary 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).
Brummelkamp
Thijn R
TR
Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
Kortlever
Roderik M
RM
Lingbeek
Merel
M
Trettel
Flavia
F
MacDonald
Marcy E
ME
van Lohuizen
Maarten
M
Bernards
René
R
D000375:Aging / Q000235:genetics*; D000818:Animals; D001847:Bone Diseases / Q000235:genetics*; D001941:Breast Diseases / Q000235:genetics*; D019556:COS Cells; D002460:Cell Line; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003342:Corpus Striatum / Q000166:cytology; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004622:Embryo, Mammalian; D005260:Female; D005786:Gene Expression Regulation; D015723:Gene Library; D019942:Genes, p16; D016158:Genes, p53; D006801:Humans; D051379:Mice; D009154:Mutation; D010920:Placenta; D011247:Pregnancy; D011401:Promoter Regions, Genetic; D012190:Retroviridae; D013489:Suppression, Genetic; D013577:Syndrome; D020825:T-Box Domain Proteins / Q000235:genetics*; D014162:Transfection; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics*
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D020825:T-Box Domain Proteins; C106884:TBX3 protein, human; C491460:Tbx3 protein, mouse; D025803:Tumor Suppressor Protein p14ARF