Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Differential acetylation of histones and transcription factors plays an important regulatory role in developmental processes, proliferation and differentiation. Aberrant acetylation or deacetylation leads to such diverse disorders as leukemia, epithelial cancers, fragile X syndrome and Rubinstein-Taybi syndrome. The various groups of histone acetyltransferases (CBP/p300, GNAT, MYST, nuclear receptor coactivators and TAFII250) and histone deacetylases are surveyed with regard to their possible or known involvement in cancer progression and human developmental disorders. Current treatment strategies are discussed, which are still mostly limited to histone deacetylase inhibitors such as trichostatin A and butyrate.
 ...
PMID:Histone acetylation and disease. 1143 34

Oncogenesis associated with human T-cell leukemia virus (HTLV) infection is directly linked to the virally encoded transcription factor Tax. To activate HTLV-1 transcription Tax interacts with the cellular protein CREB and the pleiotropic coactivators CBP and p300. While extensively studied, the molecular mechanisms of Tax transcription function and coactivator utilization are not fully understood. Previous studies have focused on Tax binding to the KIX domain of CBP, as this was believed to be the key step in recruiting the coactivator to the HTLV-1 promoter. In this study, we identify a carboxy-terminal region of CBP (and p300) that strongly interacts with Tax and mediates Tax transcription function. Through deletion mutagenesis, we identify amino acids 2003 to 2212 of CBP, which we call carboxy-terminal region 2 (CR2), as the minimal region for Tax interaction. Interestingly, this domain corresponds to the steroid receptor coactivator 1 (SRC-1)-interacting domain of CBP. We show that a double point mutant targeted to one of the putative alpha-helical motifs in this domain significantly compromises the interaction with Tax. We also characterize the region of Tax responsible for interaction with CR2 and show that the previously identified transactivation domain of Tax (amino acids 312 to 319) participates in CR2 binding. This region of Tax corresponds to a consensus amphipathic helix, and single point mutations targeted to amino acids on the face of this helix abolish interaction with CR2 and dramatically reduce Tax transcription function. Finally, we demonstrate that Tax and SRC-1 bind to CR2 in a mutually exclusive fashion. Together, these studies identify a novel Tax-interacting site on CBP/p300 and extend our understanding of the molecular mechanism of Tax transactivation.
 ...
PMID:The oncoprotein Tax binds the SRC-1-interacting domain of CBP/p300 to mediate transcriptional activation. 1146 34

Efficient transcription of the human T-cell leukemia virus type 1 (HTLV-1) genome requires Tax, a virally encoded oncogenic transcription factor, in complex with the cellular transcription factor CREB and the coactivators p300/CBP. To examine Tax transactivation in vitro, we used a chromatin assembly system that included recombinant core histones. The addition of Tax, CREB, and p300 to the HTLV-1 promoter assembled into chromatin activated transcription several hundredfold. Chromatin templates selectively lacking amino-terminal histone tails demonstrated enhanced transcriptional activation by Tax and CREB, with significantly reduced dependence on p300 and acetyl coenzyme A (acetyl-CoA). Interestingly, Tax/CREB activation from the tailless chromatin templates retained a substantial requirement for acetyl-CoA, indicating a role for acetyl-CoA beyond histone acetylation. These data indicate that during Tax transcriptional activation, the amino-terminal histone tails are the major targets of p300 and that tail deletion and acetylation are functionally equivalent.
 ...
PMID:p300-mediated tax transactivation from recombinant chromatin: histone tail deletion mimics coactivator function. 1173 28

The AML1-CBF beta transcription factor complex is the most frequent target of specific chromosome translocations in human leukemia. The MOZ gene, which encodes a histone acetyltransferase (HAT), is also involved in some leukemia-associated translocations. We report here that MOZ is part of the AML1 complex and strongly stimulates AML1-mediated transcription. The stimulation of AML1-mediated transcription is independent of the inherent HAT activity of MOZ. Rather, a potent transactivation domain within MOZ appears to be essential for stimulation of AML1-mediated transcription. MOZ, as well as CBP and MOZ-CBP, can acetylate AML1 in vitro. The amount of AML1-MOZ complex increases during the differentiation of M1 myeloid cells into monocytes/macrophages, suggesting that the AML1-MOZ complex might play a role in cell differentiation. On the other hand, the MOZ-CBP fusion protein, which is created by the t(8;16) translocation associated with acute monocytic leukemia, inhibits AML1-mediated transcription and differentiation of M1 cells. These results suggest that MOZ-CBP might induce leukemia by antagonizing the function of the AML1 complex.
 ...
PMID:Activation of AML1-mediated transcription by MOZ and inhibition by the MOZ-CBP fusion protein. 1174 95

Promyelocytic leukaemia (PML) nuclear bodies are present in most mammalian cell nuclei. PML bodies are disrupted by PML retinoic acid receptor alpha (RAR alpha) oncoproteins in acute promyelocytic leukaemia. These bodies contain numerous proteins, including Sp100, SUMO-1, HAUSP(USP7), CBP and BLM, and they have been implicated in aspects of transcriptional regulation or as nuclear storage depots. Here, we show that three classes of PML nuclear bodies can be distinguished, on the basis of their dynamic properties in living cells. One class of PML bodies is particularly noteworthy in that it moves by a metabolic-energy-dependent mechanism. This represents the first example of metabolic-energy-dependent transport of a nuclear body within the mammalian cell nucleus.
 ...
PMID:Metabolic-energy-dependent movement of PML bodies within the mammalian cell nucleus. 1175 75

The tumor suppressor p53 recruits the cellular coactivator CBP/p300 to mediate the transcriptional activation of target genes. In this study, we identify a novel p53-interacting region in CBP/p300, which we call CR2, located near the carboxyl terminus. The 95-amino acid CR2 region (amino acids 2055--2150) is located adjacent to the C/H3 domain and corresponds precisely with the minimal steroid receptor coactivator 1 (SRC1)-interacting domain of CBP (also called IBiD). We show that the region of p53 that participates in the CR2 interaction resides within the first 107 amino acids of the protein. p53 binds strongly to the CR2 domain of both CBP and the highly homologous coactivator p300. Importantly, an in-frame deletion of CR2 within the full-length p300 protein strongly compromises p300-mediated p53 transcriptional activation from a chromatin template in vitro. The identification of the p53-interacting CR2 domain in CBP/p300 prompted us to ask if the human T-cell leukemia virus (HTLV-I) Tax protein, which also interacts with CR2, competes with p53 for binding to this domain. We show that p53 and Tax exhibit mutually exclusive binding to the CR2 region, possibly contributing to the previously reported Tax repression of p53 function. Together, these studies identify and molecularly characterize a new p53 binding site on CBP/p300 that participates in coactivator-mediated p53 transcription function. The identity of the p53.CR2 interaction indicates that at least three distinct sites on CBP/p300 may participate in mediating p53 transactivation.
 ...
PMID:p53 Transcriptional activity is mediated through the SRC1-interacting domain of CBP/p300. 1178 67

Expression of human T-cell leukemia virus type 1 (HTLV-1) is regulated by the viral transcriptional activator Tax. Tax activates viral transcription through interaction with the cellular transcription factor CREB and the coactivators CBP/p300. One key property of the coactivators is the presence of histone acetyltransferase (HAT) activity, which enables p300/CBP to modify nucleosome structure. The data presented in this manuscript demonstrate that full-length p300 and CBP facilitate transcription of a reconstituted chromatin template in the presence of Tax and CREB. The ability of p300 and CBP to activate transcription from the chromatin template is dependent upon the HAT activity. Moreover, the coactivator HAT activity must be tethered to the template by Tax and CREB, since a p300 mutant that fails to interact with Tax did not facilitate transcription or acetylate histones. p300 acetylates histones H3 and H4 within nucleosomes located in the promoter and 5' proximal regions of the template. Nucleosome acetylation is accompanied by an increase in the level of binding of RNA polymerase II transcription factor TFIID and RNA polymerase II to the promoter. Interestingly, we found distinct transcriptional activities between CBP and p300. CBP, but not p300, possesses an N-terminal activation domain which directly activates Tax-mediated HTLV-1 transcription from a naked DNA template. Finally, using the chromatin immunoprecipitation assay, we provide the first direct experimental evidence that p300 and CBP are associated with the HTLV-1 long terminal repeat in vivo.
 ...
PMID:Acetylation of nucleosomal histones by p300 facilitates transcription from tax-responsive human T-cell leukemia virus type 1 chromatin template. 1205 56

We have previously demonstrated that the bZIP transcription factor CREB-2, also called ATF-4, trans-activates, in association with the viral protein Tax, the human T-cell leukemia virus type I (HTLV-I) promoter. In this study, we have examined whether CREB-2 acetylation affects transcriptional activation mediated by Tax. We present evidence that CREB-2 is acetylated in vitro and in vivo. CREB-2 is acetylated in two regions: the basic domain of the bZIP (from amino acid residue 270 to 300) and the short basic domain (from 342 to 351) located downstream from the bZIP. We also demonstrate that CREB-2 is acetylated by p300/CBP but not by p/CAF. Moreover, replacement of lysine by arginine in the basic domains decreases the trans-activating capacity of CREB-2. However, in the presence of Tax, the HTLV-I transcription remains fully activated by these CREB-2 mutants. Although we cannot totally exclude that the mutations could also affect CREB-2 structure and activity independent of acetylation, our results suggest that activation of the viral promoter in the presence of Tax is independent of the CREB-2 acetylation.
 ...
PMID:Activation of HTLV-I transcription in the presence of Tax is independent of the acetylation of CREB-2 (ATF-4). 1220 30

The interactions between cAMP-response element-binding protein (CREB)-binding protein (CBP) and gene-specific transcription factors play an important role in activation of transcription from numerous genes. Cooperative interactions between CBP and multiple transcriptional activators may provide a mechanism for synergistic increases in transcriptional activation. Here we report the characterization of ternary complexes formed by the KIX domain of CBP and the transactivation domain of the trithorax group protein mixed lineage leukemia protein (MLL), together with either the phosphorylated kinase-inducible domain (pKID) of CREB or the activation domain from c-Myb. Isothermal titration calorimetry experiments show that KIX in complex with the MLL activation domain binds the c-Myb activation domain and pKID domain with 2-fold higher affinity than does the KIX domain alone. Thus, the activation domains of Myb and MLL or of pKID and MLL bind cooperatively to KIX. The thermodynamics of these interactions imply different mechanisms of binding cooperativity for the two ternary complexes; the KIX.MLL.pKID complex is stabilized by entropy increases, whereas the enhancement of Myb binding in the presence of the MLL activation domain is due to more favorable enthalpy. NMR experiments show that the MLL-binding site on KIX is distinct from the surface that binds the pKID and c-Myb activation domains. Our data indicate that KIX can directly mediate cooperative interactions between pairs of transcriptional regulatory proteins. In the case of MLL and c-Myb, both proteins are involved in proliferation of hematopoietic cells and leukemogenesis, and synergistic interactions mediated by CBP may play a functional role.
 ...
PMID:Cooperativity in transcription factor binding to the coactivator CREB-binding protein (CBP). The mixed lineage leukemia protein (MLL) activation domain binds to an allosteric site on the KIX domain. 1220 94

Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are known to interact with several transcription factors and regulate their transcriptional activities. The human T-cell leukemia virus type 1 (HTLV-1) Tax oncoprotein activates transcription from its long terminal repeat (LTR) through interaction with cellular factors such as CREB and a transcriptional coactivator CBP/p300. However, little is known about the interaction between Tax and transcriptional repressors. Here, we demonstrate the physical and functional interaction between Tax and HDAC1. We found that HDAC1 represses the trans-activation function of Tax in 293T and MT4 cells. However, this repression was restored by treatment with an HDAC inhibitor, Trichostatin A. We also observed physical interaction between Tax and HDAC1 both in vitro and in vivo. The N-terminal region of HDAC1 (amino acid residues 28-97) was required for this binding. Moreover, HDAC1 inhibited the synergistic trans-activation of Tax observed on ectopic expression of CBP. However, this repression was relieved by overexpression of CBP. Thus, HDAC1 is likely to compete with CBP in binding with Tax and functions as a negative regulator for the transcriptional activation by Tax.
 ...
PMID:The interaction of HTLV-1 Tax with HDAC1 negatively regulates the viral gene expression. 1237 Aug 15


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>