NIR, an inhibitor of histone acetyltransferases, regulates transcription factor TAp63 and is controlled by the cell cycle.
p63 Is a sequence-specific transcription factor that regulates epithelial stem cell maintenance and epithelial differentiation. In addition, the TAp63 isoform with an N-terminal transactivation domain functions as an inducer of apoptosis during the development of sympathetic neurons. Previous work has indicated that the co-activator and histone acetyltransferase (HAT), p300, can bind to TAp63 and stimulate TAp63-dependent transcription of the p21Cip1 gene. Novel INHAT Repressor (NIR) is an inhibitor of HAT. Here, we report that the central portion of NIR binds to the transactivation domain and the C-terminal oligomerization domain of TAp63. NIR is highly expressed in G2/M phase of the cell cycle and only weakly expressed in G1/S. Furthermore, except during mitosis, NIR is predominantly localized in the nucleolus; only a small portion co-localizes with TAp63 in the nucleoplasm and at the p21 gene promoter. Consistent with NIR acting as a repressor, the induced translocation of NIR from the nucleolus into the nucleoplasm resulted in the inhibition of TAp63-dependent transactivation of p21. Conversely, knockdown of NIR by RNAi stimulated p21 transcription in the presence of TAp63. Thus, NIR is a cell-cycle-controlled, novel negative regulator of TAp63. The low levels of nucleoplasmic NIR might act as a buffer toward potentially toxic TAp63.
Heyne
Kristina
K
José Carreras Research Center, Bldg 45.3, University of Saarland Medical School, 66421 Homburg/Saar, Germany.
Willnecker
Vivienne
V
Schneider
Julia
J
Conrad
Marcel
M
Raulf
Nina
N
Schüle
Roland
R
Roemer
Klaus
K
D002453:Cell Cycle / Q000235:genetics*; D002466:Cell Nucleolus / Q000378:metabolism; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015533:Transcriptional Activation
D050759:Cyclin-Dependent Kinase Inhibitor p21; C507220:NOC2L protein, human; D012097:Repressor Proteins; D015534:Trans-Activators; D051548:Histone Acetyltransferases