scholarly journals Adenovirus E1A specifically blocks SWI/SNF-dependent transcriptional activation.

1996 ◽  
Vol 16 (10) ◽  
pp. 5737-5743 ◽  
Author(s):  
M E Miller ◽  
B R Cairns ◽  
R S Levinson ◽  
K R Yamamoto ◽  
D A Engel ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Cellular Transformation ◽  
Transcriptional Coactivator ◽  
Gene Encoding ◽  
Adenovirus E1a ◽  
Transcriptional Regulatory ◽  
Genes Encoding ◽  
Regulatory Complex ◽  
Activation Pathways ◽  
Coactivator P300

Expression of the adenovirus E1A243 oncoprotein in Saccharomyces cerevisiae produces a slow-growth phenotype with accumulation of cells in the G1 phase of the cell cycle. This effect is due to the N-terminal and CR1 domains of E1A243, which in rodent cells are involved in triggering cellular transformation and also in binding to the cellular transcriptional coactivator p300. A genetic screen was undertaken to identify genes required for the function of E1A243 in S. cerevisiae. This screen identified SNF12, a gene encoding the 73-kDa subunit of the SWI/SNF transcriptional regulatory complex. Mutation of genes encoding known members of the SWI/SNF complex also led to loss of E1A function, suggesting that the SWI/SNF complex is a target of E1A243. Moreover, expression of E1A in wild-type cells specifically blocked transcriptional activation of the INO1 and SUC2 genes, whose activation pathways are distinct but have a common requirement for the SWI/SNF complex. These data demonstrate a specific functional interaction between E1A and the SWI/SNF complex and suggest that a similar interaction takes place in rodent and human cells.

scholarly journals AMF-1/Gps2 Binds p300 and Enhances Its Interaction with Papillomavirus E2 Proteins

2000 ◽  
Vol 74 (13) ◽  
pp. 5872-5879 ◽  
Author(s):  
Yu-Cai Peng ◽  
David E. Breiding ◽  
Francis Sverdrup ◽  
James Richard ◽  
Elliot J. Androphy
Keyword(s):  
Gene Expression ◽  
Transcriptional Activation ◽  
Functional Significance ◽  
Cellular Protein ◽  
Transcriptional Coactivator ◽  
Adenovirus E1a ◽  
Coactivator P300 ◽  
P300 Recruitment

ABSTRACT The cellular protein AMF-1 (Gps2) positively modulates gene expression by the papillomavirus E2 protein (D. E. Breiding et al., Mol. Cell. Biol. 17:7208–7219, 1997). We show here that AMF-1 also binds the transcriptional coactivator p300 in vitro and in vivo. E2 interacted weakly with p300. These observations led to a model in which AMF-1 recruits p300 into a complex with E2. Cotransfection of AMF-1 or p300 stimulated levels of E2-dependent transcription, while cotransfection of both AMF-1 and p300 showed an additive effect. The functional significance of p300 recruitment for E2 transactivation was evidenced by repression of E2-activated transcription by adenovirus E1A, which inhibits both coactivator and acetylase activities of p300. Antibodies to AMF-1 or E2 immunoprecipitated histone acetylase activity from cell lysates. Western blotting using antibody against acetyl-lysine failed to detect acetylation of AMF-1 or E2 in complex with p300. These results suggest that AMF-1 facilitates the recruitment of p300 and its histone acetylase activity into complexes with E2 and represents a novel mechanism of transcriptional activation.

HDAC1-Smad3-mSin3Acomplex is required for Smad3-induced transcriptional inhibition of hepatocyte growth factor receptor in human lung cancers

2020 ◽  
Author(s):  
Hao-Xin Gui ◽  
Jun Peng ◽  
Ze-Ping Yang ◽  
Lu-Yao Chen ◽  
Hong Zeng ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Molecular Mechanisms ◽  
Growth Factor Receptor ◽  
Mrna Levels ◽  
Lung Cancers ◽  
Transcriptional Inhibition ◽  
Transcriptional Suppression ◽  
Transcriptional Regulatory ◽  
Regulatory Complex ◽  
Cancer Tissues

Abstract c-Met hyperactivity has been observed in numerous neoplasms. Several researchers have shown that the abnormal activation of c-Met is mainly caused by transcriptional activation. However, the molecular mechanism behind this transcriptional regulation is poorly understood. Here, we suggest that Smad3 negatively regulates the expression and activation of c-Met via a transcriptional mechanism. We explore the molecular mechanisms that underlie Smad3-induced c-Met transcription inhibition. We found in contrast to the high expression of c-Met, Smad3 showed low protein and mRNA levels. Smad3 and c-Met expression was inconsistent between lung cancer tissues and cell lines. We also found that Smad3 overexpression suppresses whereas Smad3 knockdown significantly promotes EMT and production of the angiogenic factors VEGF, CTGF and COX-2 through the ERK1/2 pathway. In addition, Smad3 overexpression decreases whereas Smad3 knockdown significantly increases protein and mRNA levels of invasion related β-catenin and FAK through the PI3K/Akt pathway. Furthermore, using the ChIP analysis method, we demonstrate that a transcriptional regulatory complex consisting of HDAC1, Smad3 and mSin3A binds to the promoter of the c-Met gene. By either silencing endogenous mSin3A expression with siRNA or by pretreating cells with a specific HDAC1 inhibitor (MS-275), Smad3-induced transcriptional suppression of c-Met could be effectively attenuated. These results demonstrate that Smad3-induced inhibition of c-Met transcription depends on of a functional transcriptional regulatory complex that includes Smad3, mSin3A and HDAC1 at the c-Met promoter. Collectively, our findings reveal a new regulatory mechanism of c-Met signaling, and suggest a potential molecular target for the development of anticancer drugs.

scholarly journals Point mutation in the gene encoding p300 suppresses thrombocytopenia in Mpl−/− mice

Blood ◽  
2008 ◽  
Vol 112 (8) ◽  
pp. 3148-3153 ◽  
Author(s):  
Maria Kauppi ◽  
James M. Murphy ◽  
Carolyn A. de Graaf ◽  
Craig D. Hyland ◽  
Kylie T. Greig ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Protein C ◽  
Lymphoid Cells ◽  
Wild Type ◽  
Gene Encoding ◽  
Mutagenesis Screen ◽  
Transcriptional Regulatory ◽  
Regulatory Complex ◽  
Transcriptional Coregulator ◽  
B Lymphoid

Abstract In an N-nitroso-N-ethylurea (ENU) mutagenesis screen using Mpl−/− mice, we isolated a semidominant suppressor of thrombocytopenia, termed Plt6. The gene mutated in Plt6 mice encodes the transcriptional coregulator p300, and the mutation, a tyrosine to asparagine substitution at amino acid 630 (Y630N), disrupts the interaction between p300 and c-Myb. Mpl−/−p300Plt6/+ mice displayed elevated platelet counts relative to Mpl−/−p300+/+ controls, whereas mice homozygous for the Plt6 mutation produced supraphysiological levels of circulating platelets. On a wild-type genetic background, mice homozygous for the p300Plt6 mutation, or recipients of Mpl+/+p300Plt6/Plt6 bone marrow, also exhibited thrombocytosis as well as deficiencies in B-lymphoid cells. Increased platelet numbers in Plt6 mutant mice were accompanied by significant increases in megakaryocyte progenitor cells within the bone marrow and spleen with concomitantly elevated numbers of megakaryocytes. The expansion of megakaryocytopoiesis and suppression of Mpl−/− thrombocytopenia in Plt6 mutants is highly reminiscent of that observed in mice with mutations affecting the p300 partner protein c-Myb, suggesting an indispensable repressive role for the c-Myb/p300 transcriptional regulatory complex in megakaryocyte develop-ment, the inhibition of which allows substantial thrombopoietin (TPO)–independent platelet production.

Selective induction of human heat shock gene transcription by the adenovirus E1A gene products, including the 12S E1A product

1987 ◽  
Vol 7 (8) ◽  
pp. 2884-2890
Author(s):  
M C Simon ◽  
K Kitchener ◽  
H T Kao ◽  
E Hickey ◽  
L Weber ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Heat Shock ◽  
Heat Shock Gene ◽  
Hsp70 Expression ◽  
Gene Encoding ◽  
S1 Nuclease ◽  
Adenovirus E1a ◽  
Genes Encoding ◽  
E1a Gene ◽  
The Individual

We have previously shown that the human 70-kilodalton heat shock protein gene (hsp70) is induced by the adenovirus E1A gene product and during the S-G2 phase of the cell cycle. In this study, we investigated the effect of E1A on the expression of other human hsp genes. A gene encoding one form of the hsp89 protein (hsp89 alpha) was activated during an adenovirus infection with kinetics similar to those of activation of hsp70. The induction required a functional E1A gene. However, the hsp89 transcript was not cell cycle regulated. Genes encoding another form of hsp89 and the hsp27 protein were not induced by E1A or during the cell cycle. Further examination of hsp70 expression revealed a greater complexity than previously seen. S1 nuclease analysis using an hsp70 cDNA as well as a distinct hsp70 genomic clone demonstrated three related hsp70 transcripts; two were induced by E1A, and one was not. Both of the E1A-inducible genes were regulated during the cell cycle. All three were induced by heat shock. These results suggest common aspects of control among certain members of this family of cellular genes distinct from heat shock control. Finally, using viruses that express the individual E1A proteins, we found that the hsp70 gene is induced by the 12S and the 13S E1A products. The efficiency of induction by the 12S product was somewhat less than that by the 13S product but only by a factor of less than 2. This is in contrast to the induction of early viral genes, for which the 13S product is considerably more efficient than the 12S product.

scholarly journals DNA Recognition by the Herpes Simplex Virus Transactivator VP16: a Novel DNA-Binding Structure

2001 ◽  
Vol 21 (14) ◽  
pp. 4700-4712 ◽  
Author(s):  
Robert Babb ◽  
C. Chris Huang ◽  
Deborah J. Aufiero ◽  
Winship Herr
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Dna Binding ◽  
Transcriptional Activation ◽  
Binding Activity ◽  
Dna Binding Activity ◽  
Transcriptional Regulatory ◽  
Regulatory Complex ◽  
Simplex Virus ◽  
Carboxy Terminal

ABSTRACT Upon infection, the herpes simplex virus (HSV) transcriptional activator VP16 directs the formation of a multiprotein-DNA complex—the VP16-induced complex—with two cellular proteins, the host cell factor HCF-1 and the POU domain transcription factor Oct-1, on TAATGARAT-containing sequences found in the promoters of HSV immediate-early genes. HSV VP16 contains carboxy-terminal sequences important for transcriptional activation and a central conserved core that is important for VP16-induced complex assembly. On its own, VP16 displays little, if any, sequence-specific DNA-binding activity. We show here that, within the VP16-induced complex, however, the VP16 core has an important role in DNA binding. Mutation of basic residues on the surface of the VP16 core reveals a novel DNA-binding surface with essential residues which are conserved among VP16 orthologs. These results illuminate how, through association with DNA, VP16 is able to interpret cis-regulatory signals in the DNA to direct the assembly of a multiprotein-DNA transcriptional regulatory complex.

scholarly journals Selective induction of human heat shock gene transcription by the adenovirus E1A gene products, including the 12S E1A product.

1987 ◽  
Vol 7 (8) ◽  
pp. 2884-2890 ◽  
Author(s):  
M C Simon ◽  
K Kitchener ◽  
H T Kao ◽  
E Hickey ◽  
L Weber ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Heat Shock ◽  
Heat Shock Gene ◽  
Hsp70 Expression ◽  
Gene Encoding ◽  
S1 Nuclease ◽  
Adenovirus E1a ◽  
Genes Encoding ◽  
E1a Gene ◽  
The Individual

We have previously shown that the human 70-kilodalton heat shock protein gene (hsp70) is induced by the adenovirus E1A gene product and during the S-G2 phase of the cell cycle. In this study, we investigated the effect of E1A on the expression of other human hsp genes. A gene encoding one form of the hsp89 protein (hsp89 alpha) was activated during an adenovirus infection with kinetics similar to those of activation of hsp70. The induction required a functional E1A gene. However, the hsp89 transcript was not cell cycle regulated. Genes encoding another form of hsp89 and the hsp27 protein were not induced by E1A or during the cell cycle. Further examination of hsp70 expression revealed a greater complexity than previously seen. S1 nuclease analysis using an hsp70 cDNA as well as a distinct hsp70 genomic clone demonstrated three related hsp70 transcripts; two were induced by E1A, and one was not. Both of the E1A-inducible genes were regulated during the cell cycle. All three were induced by heat shock. These results suggest common aspects of control among certain members of this family of cellular genes distinct from heat shock control. Finally, using viruses that express the individual E1A proteins, we found that the hsp70 gene is induced by the 12S and the 13S E1A products. The efficiency of induction by the 12S product was somewhat less than that by the 13S product but only by a factor of less than 2. This is in contrast to the induction of early viral genes, for which the 13S product is considerably more efficient than the 12S product.

scholarly journals A Cellular Repressor of E1A-Stimulated Genes That Inhibits Activation by E2F

1998 ◽  
Vol 18 (9) ◽  
pp. 5032-5041 ◽  
Author(s):  
Elizabeth Veal ◽  
Michael Eisenstein ◽  
Zian H. Tseng ◽  
Grace Gill
Keyword(s):  
Transcriptional Activation ◽  
Transcriptional Control ◽  
Cell Cycle Progression ◽  
Cellular Proliferation ◽  
Sequence Similarity ◽  
Cellular Transformation ◽  
Cellular Protein ◽  
Adenovirus E1a ◽  
E1a Protein

ABSTRACT The adenovirus E1A protein both activates and represses gene expression to promote cellular proliferation and inhibit differentiation. Here we report the identification and characterization of a cellular protein that antagonizes transcriptional activation and cellular transformation by E1A. This protein, termed CREG for cellular repressor of E1A-stimulated genes, shares limited sequence similarity with E1A and binds both the general transcription factor TBP and the tumor suppressor pRb in vitro. In transfection assays, CREG represses transcription and antagonizes 12SE1A-mediated activation of both the adenovirus E2 and cellular hsp70 promoters. CREG also antagonizes E1A-mediated transformation, as expression of CREG reduces the efficiency with which E1A and the oncogeneras cooperate to transform primary cells. Binding sites for E2F, a key transcriptional regulator of cell cycle progression, were found to be required for repression of the adenovirus E2 promoter by CREG, and CREG was shown to inhibit activation by E2F. Since both the adenovirus E1A protein and transcriptional activation by E2F function to promote cellular proliferation, the results presented here suggest that CREG activity may contribute to the transcriptional control of cell growth and differentiation.

scholarly journals Clustering of the YNA1 gene encoding a Zn(II)2Cys6 transcriptional factor in the yeast Hansenula polymorpha with the nitrate assimilation genes YNT1, YNI1 and YNR1, and its involvement in their transcriptional activation

1998 ◽  
Vol 335 (3) ◽  
pp. 647-652 ◽  
Author(s):  
Julio ÁVILA ◽  
Celedonio GONZÁLEZ ◽  
Nélida BRITO ◽  
José M. SIVERIO
Keyword(s):  
Transcriptional Activation ◽  
Hansenula Polymorpha ◽  
Nitrate Assimilation ◽  
Transcriptional Factors ◽  
Gene Encoding ◽  
Reading Frame ◽  
Transcription Start Sites ◽  
The Family ◽  
Genes Encoding ◽  
Free Media

The genes encoding the nitrate transporter (YNT1), nitrite reductase (YNI1) and nitrate reductase (YNR1) are clustered in the yeast Hansenula polymorpha. In addition, DNA sequencing of the region containing these genes demonstrated that a new open reading frame called YNA1 (yeast nitrate assimilation) was located between YNR1 and YNI1. The YNA1 gene encodes a protein of 529 residues belonging to the family of Zn(II)2Cys6 fungal transcriptional factors, and has the highest similarity to the transcriptional factors encoded by nirA, and to a smaller extent to nit-4, involved in the nitrate induction of the gene involved in the assimilation of this compound in filamentous fungi. Northern blot analysis showed the presence of the YNA1 transcript in cells incubated in nitrate, nitrate plus ammonium, ammonium, and nitrogen-free media, with a decrease in its levels in those cells incubated in ammonium. In nitrate the strain Δyna1::URA3, with a disrupted YNA1 gene, neither grew nor expressed the genes YNT1, YNI1 and YNR1. In the gene cluster YNT1-YNI1-YNA1-YNR1, the four genes were transcribed independently in the YNT1 → YNR1 direction and the transcription start sites were determined by primer extension.

scholarly journals The Adenovirus E1A Protein Targets the SAGA but Not the ADA Transcriptional Regulatory Complex through Multiple Independent Domains

2002 ◽  
Vol 277 (34) ◽  
pp. 30844-30851 ◽  
Author(s):  
Michael Shuen ◽  
Nikita Avvakumov ◽  
Paul G. Walfish ◽  
Chris J. Brandl ◽  
Joe S. Mymryk
Keyword(s):  
Protein Targets ◽  
Adenovirus E1a ◽  
Transcriptional Regulatory ◽  
Regulatory Complex ◽  
E1a Protein

scholarly journals Purification and Characterization of the Repressor of the Shiga Toxin-Encoding Bacteriophage 933W: DNA Binding, Gene Regulation, and Autocleavage

2004 ◽  
Vol 186 (22) ◽  
pp. 7659-7669 ◽  
Author(s):  
Astrid P. Koudelka ◽  
Lisa A. Hufnagel ◽  
Gerald B. Koudelka
Keyword(s):  
Dna Binding ◽  
Shiga Toxin ◽  
Binding Activity ◽  
Purification And Characterization ◽  
Gene Encoding ◽  
Dna Binding Activity ◽  
Transcriptional Regulatory ◽  
Genes Encoding ◽  
Lambdoid Prophage

ABSTRACT The genes encoding Shiga toxin (stx), the major virulence factor of Shiga toxin-encoding Escherichia coli (STEC) strains, are carried on lambdoid prophages resident in all known STEC strains. The stx genes are expressed only during lytic growth of these temperate bacteriophages. We cloned the gene encoding the repressor of the Shiga toxin-encoding bacteriophage 933W and examined the DNA binding and transcriptional regulatory activities of the overexpressed, purified protein. Typical of nearly all lambdoid phage repressors, 933W repressor binds to three sites in 933W right operator (OR). Also typical, when bound at OR, 933W repressor functions as an activator at the PRM promoter and a repressor at the PR promoter. In contrast to other lambdoid bacteriophages, 933W left operator (OL) contains only two repressor binding sites, but the OL-bound repressor still efficiently represses PL transcription. Lambdoid prophage induction requires inactivation of the repressor's DNA binding activity. In all phages examined thus far, this inactivation requires a RecA-stimulated repressor autoproteolysis event, with cleavage occurring precisely in an Ala-Gly dipeptide sequence that is found within a “linker ” region that joins the two domains of these proteins. However, 933W repressor protein contains neither an Ala-Gly nor an alternative Cys-Gly dipeptide cleavage site anywhere in its linker sequence. We show here that the autocleavage occurs at a Leu-Gly dipeptide. Thus, the specificity of the repressor autocleavage site is more variable than thought previously.

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