Tbx2 directly represses the expression of the p21(WAF1) cyclin-dependent kinase inhibitor.
T-box factors play a crucial role in the development of many tissues, and mutations in T-box factor genes have been implicated in multiple human disorders. Some T-box factors have been implicated in cancer; for example, Tbx2 and Tbx3 can suppress replicative senescence, whereas Tbx3 can cooperate with Myc and Ras in cellular transformation. The p21(WAF1) cyclin-dependent kinase inhibitor plays a key role in senescence and in cell cycle arrest after DNA damage. Here, using a combination of in vitro DNA-binding, transfection, and chromatin immunoprecipitation assays, we show that Tbx2 can bind and repress the p21 promoter in vitro and in vivo. Moreover, small interfering RNA-mediated down-regulation of Tbx2 expression results in a robust activation of p21 expression. Taken together, these results implicate Tbx2 as a novel direct regulator of p21 expression and have implications for our understanding of the role of T-box factors in the regulation of senescence and oncogenesis, as well as in development.
Prince
Sharon
S
Signalling and Development Laboratory, Marie Curie Research Institute, Oxted, Surrey, United Kingdom.
Carreira
Suzanne
S
Vance
Keith W
KW
Abrahams
Amaal
A
Goding
Colin R
CR
D000818:Animals; D019556:COS Cells; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics*; D005786:Gene Expression Regulation; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000502:physiology*; D020825:T-Box Domain Proteins / Q000502:physiology*
D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D012097:Repressor Proteins; C097348:T-Box Domain Protein 2; D020825:T-Box Domain Proteins