The C-terminal sterile α motif and the extreme C terminus regulate the transcriptional activity of the α isoform of p73

被引:53
作者
Liu, G [1 ]
Chen, XB [1 ]
机构
[1] Univ Alabama Birmingham, Dept Cell Biol, Birmingham, AL 35294 USA
关键词
D O I
10.1074/jbc.M413889200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
p73, a member of the p53 family, is expressed from two separate promoters, generating TA and Delta N variants. Each variant potentially encodes at least seven alternatively spliced isoforms (alpha-eta). Interestingly, we and others have shown that the alpha isoform of p73 has a weaker transcriptional activity than the beta isoform. Because the alpha isoform has an extended C terminus consisting of a sterile alpha motif (SAM) and an extreme C terminus, it appears that the C terminus is inhibitory. However, how the C terminus inhibits the transcriptional activity of p73 has not been determined. Here, we found that both the SAM and the extreme C terminus exert their inhibitory activity by preventing the accessibility of p300/CBP to the activation domain in p73. Specifically, we showed that the SAM and the extreme C terminus together or individually are capable of repressing the function of p73 activation domain, but neither interacts directly with the activation domain, or suppresses the DNA-binding activity, of the p73 protein. We also showed that the intact state of the SAM and the extreme C terminus is essential for their inhibitory functions such that a small deletion of either the SAM or the extreme C terminus abolishes its inhibitory activity. Furthermore, we showed that both inhibitory domains in the C terminus are capable of suppressing the function of a cis heterologous activation domain from p53 or Gal4. Finally, we showed that both inhibitory domains suppress the ability of p73 to interact with the transcriptional coactivators p300/CBP that are necessary for the initiation of transcription.
引用
收藏
页码:20111 / 20119
页数:9
相关论文
共 62 条
[1]  
Agami R, 1999, NATURE, V399, P809
[2]   Induction of p57KIP2 expression by p73β [J].
Bálint, É ;
Phillips, AC ;
Kozlov, S ;
Stewart, CL ;
Vousden, KH .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (06) :3529-3534
[3]   Acetylation of p53 activates transcription through recruitment of coactivators/histone acetyltransferases [J].
Barlev, NA ;
Liu, L ;
Chehab, NH ;
Mansfield, K ;
Harris, KG ;
Halazonetis, TD ;
Berger, SL .
MOLECULAR CELL, 2001, 8 (06) :1243-1254
[4]   ASPP1 and ASPP2: Common activators of p53 family members [J].
Bergamaschi, D ;
Samuels, Y ;
Jin, BQ ;
Duraisingham, S ;
Crook, T ;
Lu, X .
MOLECULAR AND CELLULAR BIOLOGY, 2004, 24 (03) :1341-1350
[5]   Ubiquitin-dependent degradation of p73 is inhibited by PML [J].
Bernassola, F ;
Salomoni, P ;
Oberst, A ;
Di Como, CJ ;
Pagano, M ;
Melino, G ;
Pandolfi, PP .
JOURNAL OF EXPERIMENTAL MEDICINE, 2004, 199 (11) :1545-1557
[6]   Predicting functions from protein sequences - where are the bottlenecks? [J].
Bork, P ;
Koonin, EV .
NATURE GENETICS, 1998, 18 (04) :313-318
[7]   Ubiquitination, phosphorylation and acetylation: the molecular basis for p53 regulation [J].
Brooks, CL ;
Gu, W .
CURRENT OPINION IN CELL BIOLOGY, 2003, 15 (02) :164-171
[8]   p53 levels, functional domains, and DNA damage determine the extent of the apoptotic response of tumor cells [J].
Chen, XB ;
Ko, LJ ;
Jayaraman, L ;
Prives, C .
GENES & DEVELOPMENT, 1996, 10 (19) :2438-2451
[9]   The p53 family: same response, different signals? [J].
Chen, XB .
MOLECULAR MEDICINE TODAY, 1999, 5 (09) :387-392
[10]   p73 is transcriptionally regulated by DNA damage, p53, and p73 [J].
Chen, XB ;
Zheng, YM ;
Zhu, JH ;
Jiang, JY ;
Wang, J .
ONCOGENE, 2001, 20 (06) :769-774