Transactivation by partial function P53 family mutants is increased by the presence of G-quadruplexes at a promoter site
Matúš VojsovičLibuše KratochvilováNatália ValkováLucie ŠislerováZeinab El RashedPaola MenichiniAlberto IngaPaola MontiVáclav Brázda
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Transcription
Loss function
P53 protein
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p53 is a master regulatory, sequence-specific transcription factor that directly controls expression of over 100 genes in response to various stress signals. Transactivation is generally considered to occur through p53 binding to a consensus response element (RE) composed of two 5′-RRRCWWGYYY-3′ decamers. Recently, studying the human angiogenesis-related gene FLT1 we discovered that p53 can mediate limited transactivation at a noncanonical 1/2 site and could synergize with the estrogen receptor (ER) acting in cis at a nearby ER 1/2 site. To address the generality of concerted transactivation by p53 and ER, the 1/2 site in the FLT1 promoter was replaced with a variety of 1/2 sites, as well as canonical weak and strong p53 REs of human target genes. The p53 transactivation of all tested sequences was greatly enhanced by ligand-activated ER acting in cis . Furthermore, enhanced transactivation extends to several cancer-associated p53 mutants with altered function, suggesting ER-dependent mutant p53 activity for at least some REs. The enhanced transactivation was also found with p63 and p73. We propose a general synergistic relationship between p53 family and ER master regulators in transactivation of p53 target canonical and noncanonical REs, which might be poorly responsive to p53 on their own. This relationship greatly expands the transcriptional master network regulated by p53 in terms of genes affected and levels of expression and has implications for the appearance and possible treatments of cancer.
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Nuclear factor of activated T cells-family proteins (NFAT1/NFATp, NFATc, NFAT3, and NFAT4/NFATx/NFATc3) play a key role in the transcription of cytokine genes and other genes during the immune response. We have defined the mechanisms of transactivation by NFAT1. NFAT1 possesses two transactivation domains whose sequences are not conserved in the other NFAT-family proteins, and a conserved DNA-binding domain that mediates the recruitment of cooperating nuclear transcription factors even when it is expressed in the absence of other regions of the protein. The activity of the NH2-terminal transactivation domain is modulated by an adjacent regulatory region that contains several conserved sequence motifs represented only in the NFAT family. Our results emphasize the multiple levels at which NFAT-dependent transactivation is regulated, and predict significant differences in the architecture of cooperative transcription complexes containing different NFAT-family proteins.
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Induction of transcription from a promoter with two upstream glucocorticoid response elements is 10- to 20-fold greater than that from a similar promoter with only one response element. We have shown that interactions involving the major transactivation domain of the glucocorticoid receptor (tau 1) are the sole determinant of such synergistic transactivation by the receptor. The other transactivation domain of the receptor (tau 2) did not mediate synergistic transactivation, and therefore the ability to synergize is operationally distinct from the transactivation function per se. The level of synergistic transactivation observed in vivo can be accounted for by the level of cooperative DNA binding seen in vitro for a glucocorticoid receptor derivative containing only the tau 1 and DNA-binding domains. Cooperative DNA binding was also observed using a tau 1-DNA-binding domain protein, which was expressed in Escherichia coli and extensively purified. Therefore, it is likely that direct protein-protein interactions between tau 1 domains mediate the cooperative DNA binding. The role of cooperative DNA binding for synergistic transactivation in vivo is discussed in relation to other possible mechanisms.
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Objective: Human cytomegalovirus (HCMV) is often isolated from HIV-1-infected patients and the two viruses can infect the same cell type giving rise to direct bidirectional interactions. Whereas the long terminal repeat (LTR) transactivation ability of HCMV immediate early gene (IE1/IE2) is well documented, no information is available on the possible role of other HCMV proteins. In this study, the activity of ppUL44, an early DNA-binding protein, on HIV LTR transactivation was investigated. Methods: HIV LTR transactivation by ppUL44 in presence or absence of HIV-1 Tat and HCMV IE1/IE2 was determined in J-Jhan and U973 cells through transient transfection experiments with a series of different expression vectors. Some experiments were also performed on U373-MG astrocytoma cells permanently transfected with UL44 or with another HCMV gene used as a control (UL55). Results: The basal transactivation activity of the HIV LTR was not influenced by the presence of ppUL44. On the contrary, the transactivation observed in the presence of Tat, IE1/IE2 or both factors in synergy was strongly downregulated by ppUL44 in a dose-dependent manner. Deletion constructs of ppUL44 demonstrated that the region of the molecule responsible for the inhibition of the LTR is located within the last 114 amino acids at the carboxyl-terminal region. Conclusions: The results obtained indicate that within the last 114 amino acids of ppUL44 there is a domain that has a negative effect on the ability of HIV-1 LTR to be activated by both its autologous transactivator Tat and the heterologous transactivator HCMV IE1/IE2 functioning individually or synergistically.
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During sporulation, Bacillus thuringiensis produces intracellular, crystalline inclusions comprised of a mixture of protoxins active on insect larvae. A major class of these protoxin genes, designated cry1, is transcribed from two overlapping promoters (BtI and BtII) utilizing RNA polymerase containing sporulation sigma factors sigma(E) and sigma(K), respectively. Fusions of these promoters to lacZ were constructed in order to analyze transcription patterns. Mutations within the -10 region of the BtII promoter (within the spacer region of the BtI promoter) which departed from the consensus -10 sequence for either sigma(E) or sigma(K) resulted in inactivation of transcription from BtII and a fivefold stimulation of transcription from BtI. In contrast, transcription from both promoters was inhibited with a change to the sigma(E) consensus. One of the "promoter-up" mutations was fused to the cry1Ac1 gene, and enhanced transcription was confirmed by Northern blotting. There was an increase in the accumulation of Cry1Ac antigen at early but not later times in sporulation in the mutant. This shift was due to the rapid turnover of much of the excessively accumulated protoxin at the early times as measured by pulse-chase labeling. As a result of the turnover and the inactivation of the BtII promoter, the mutant produced smaller inclusions which contained two- to threefold-less protoxin than inclusions from the wild type. Promoter overlap is a mechanism for modulating protoxin synthesis, thus ensuring the efficient packaging of these protoxins into inclusions.
Bacillus thuringiensis
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We investigated the suppression, transformation, and transactivation functions of isolated segments of wild-type murine p53. Intact p53, but no segment of p53, inhibited cellular transformation by the activated ras and adenovirus E1A proteins. We conclude that most of p53 is needed for suppression of cellular proliferation. Nevertheless, the transactivating domain of herpesvirus protein VP16 was able to substitute for the N-terminal transactivating domain of p53 in cellular suppression. Thus, unless the interchanged p53 and VP16 acidic segments share additional functions, transactivation is required for suppression by p53. Interestingly, we found that all p53 segments containing amino acids 320-360 enhanced transformation by ras and E1A. This region has been associated with the oligomerization of p53 (Milner et al., 1991; Sturzbecher et al., 1992). Furthermore, no p53 segment lacking amino acids 320-360 transformed cells. Amino acids 320-360, therefore, may account for the major transforming activity of p53. Intact p53 and chimeric VP16-p53 transactivated the CAT gene under control of a p53-specific promoter, while transforming segments of p53 interfered with transactivation by wild-type p53. Our findings argue that transactivation by p53 is required for cellular suppression and that any nontransactivating p53 that retains the capacity to oligomerize with wild-type p53 would have transformation potential.
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