May function as a general inhibitor of the histone deacetylase HDAC1. Binding to the pocket region of RB1 may displace HDAC1 from RB1/E2F complexes, leading to activation of E2F target genes and cell cycle progression. Conversely, displacement of HDAC1 from SP1 bound to the CDKN1A promoter leads to increased expression of this CDK inhibitor and blocks cell cycle progression. Also antagonizes PAWR mediated induction of aberrant amyloid peptide production in Alzheimer disease (presenile and senile dementia), although the molecular basis for this phenomenon has not been described to date.
Aggregation of the neurotoxic amyloid beta peptide 1-42 (Abeta-(1-42)) in the brain is considered to be an early event in the pathogenesis of Alzheimer's disease (AD). Par-4 (prostate apoptosis response-4) is a leucine zipper protein that is pro-apoptotic and associated with neuronal degeneration in AD. Overexpression of Par-4 significantly increased production of Abeta-(1-42) after initiation of apoptotic cascades, indicating factors regulating apoptotic pathways may also affect processing of beta-amyloid precursor protein (APP). AATF (apoptosis-antagonizing transcription factor) was recently identified as an interaction partner of DAP-like kinase (Dlk), a member of the DAP (death-associated protein) kinase family. AATF antagonizes apoptosis induced by Par-4, suggesting that AATF might directly or indirectly participate in regulation of Par-4 activity. We now report that AATF colocalizes with Par-4 in both cytoplasmic and nuclear compartments, and it interacts directly and selectively with Par-4 via the leucine zipper domain in neural cells. Par-4 induced an aberrant production and secretion of Abeta in neuroblastoma IMR-32 cells after apoptotic cascades are initiated. Co-expression of AATF completely blocked aberrant production and secretion of Abeta-(1-42) induced by Par-4, and AATF/Par-4 complex formation was essential for the inhibitory effect of AATF on aberrant Abeta secretion. These results indicate that AATF is an endogenous antagonist of Par-4 activity and an effective inhibitor of aberrant Abeta production and secretion under apoptotic conditions.
Extensive loss of neurons and synapses in vulnerable regions of the brain is one of the most important pathological features of Alzheimer's disease (AD). Increased oxidative stress has been shown to contribute to the neurodegenerative process in AD. Aggregation of amyloid beta-peptide (Abeta) in amyloid plaques is one of the defining features of Alzheimer's disease. Indeed, Abeta has been shown to induce oxidative stress and apoptosis in many in vivo and in vitro models of AD. We now report that AATF (apoptosis-antagonizing transcription factor), a leucine zipper protein initially identified as an interaction partner of DAP like kinase (Dlk, a member of the pro-apoptotic Death-Associated Protein kinase family), is expressed in cortical neurons and in neural PC12 cells. Abeta induces alterations in AATF expression in cortical neurons. Inhibition of AATF induction sensitizes neurons to Abeta toxicity. Overexpression of AATF suppressed superoxide production, inhibited peroxynitrite formation and membrane lipid peroxidation, and protected against Abeta-induced apoptosis in PC12 cells. These results suggest that AATF is a novel neuroprotective factor and it may protect against Abeta-induced apoptosis through its effects on suppressing the production of reactive oxygen species (ROS). AATF may therefore represent a potential candidate for therapeutic intervention of neurodegeneration in both sporadic and familial forms of AD.
Che-1 is a recently identified human RNA polymerase II binding protein involved in the regulation of gene transcription and cell proliferation. We previously demonstrated that Che-1 inhibits the Rb growth-suppressing function by interfering with Rb-mediated HDAC1 recruitment on E2F target gene promoters. By hybridization of cancer profile arrays, we found that Che-1 expression is strongly down-regulated in several tumors, including colon and kidney carcinomas, compared with the relative normal tissues. Consistent with these data, Che-1 overexpression inhibits proliferation of HCT116 and LoVo human colon carcinoma cell lines by activation of the cyclin-dependent kinase inhibitor p21WAF1/Cip1 in a p53-independent manner and by promoting growth arrest at the G1 phase of the cell cycle. Che-1 activates p21WAF1/Cip1 by displacing histone deacetylase (HDAC)1 from the Sp1 binding sites of the p21WAF1/Cip1 gene promoter and accumulating acetylated histone H3 on these sites. Accordingly, Che-1-specific RNA interference negatively affects p21WAF1/Cip1 transactivation and increases cell proliferation in HCT116 cells. Taken together, our results indicate that Che-1 can be considered a general HDAC1 competitor and its down-regulation is involved in colon carcinoma cell proliferation.
DNA tumor virus oncoproteins bind and inactivate Rb by interfering with the Rb/HDAC1 interaction. Che-1 is a recently identified human Rb binding protein that inhibits the Rb growth suppressing function. Here we show that Che-1 contacts the Rb pocket region and competes with HDAC1 for Rb binding site, removing HDAC1 from the Rb/E2F complex in vitro and from the E2F target promoters in vivo. Che-1 overexpression activates DNA synthesis in quiescent NIH-3T3 cells through HDAC1 displacement. Consistently, Che-1-specific RNA interference affects E2F activity and cell proliferation in human fibroblasts but not in the pocket protein-defective 293 cells. These findings indicate the existence of a pathway of Rb regulation supporting Che-1 as the cellular counterpart of DNA tumor virus oncoproteins.
Interacting selectively and non-covalently with a leucine zipper domain, a protein secondary structure exhibiting a periodic repetition of leucine residues at every seventh position over a distance covering eight helical turns.
Evidence
1:
Inferred from Physical InteractionUniProtKB
Aggregation of the neurotoxic amyloid beta peptide 1-42 (Abeta-(1-42)) in the brain is considered to be an early event in the pathogenesis of Alzheimer's disease (AD). Par-4 (prostate apoptosis response-4) is a leucine zipper protein that is pro-apoptotic and associated with neuronal degeneration in AD. Overexpression of Par-4 significantly increased production of Abeta-(1-42) after initiation of apoptotic cascades, indicating factors regulating apoptotic pathways may also affect processing of beta-amyloid precursor protein (APP). AATF (apoptosis-antagonizing transcription factor) was recently identified as an interaction partner of DAP-like kinase (Dlk), a member of the DAP (death-associated protein) kinase family. AATF antagonizes apoptosis induced by Par-4, suggesting that AATF might directly or indirectly participate in regulation of Par-4 activity. We now report that AATF colocalizes with Par-4 in both cytoplasmic and nuclear compartments, and it interacts directly and selectively with Par-4 via the leucine zipper domain in neural cells. Par-4 induced an aberrant production and secretion of Abeta in neuroblastoma IMR-32 cells after apoptotic cascades are initiated. Co-expression of AATF completely blocked aberrant production and secretion of Abeta-(1-42) induced by Par-4, and AATF/Par-4 complex formation was essential for the inhibitory effect of AATF on aberrant Abeta secretion. These results indicate that AATF is an endogenous antagonist of Par-4 activity and an effective inhibitor of aberrant Abeta production and secretion under apoptotic conditions.
Evidence
2:
Inferred from Physical InteractionUniProtKB
Dlk, also known as ZIP kinase, is a serine/threonine kinase that is tightly associated with nuclear structures. Under certain conditions, which require cytoplasmic localization, Dlk can induce apoptosis. In search for interaction partners that might serve as regulators or targets of this kinase we identified apoptosis antagonizing transcription factor (AATF), a nuclear phosphoprotein of 523 amino acids. The 1.8 kb mRNA seems to be ubiquitously expressed. AATF contains an extremely acidic domain and a putative leucine zipper characteristic of transcription factors. Indeed, a Gal4-BD-AATF fusion protein exhibited strong transactivation activity. Interestingly, AATF interfered with Dlk-induced apoptosis.
Interacting selectively and non-covalently with any protein or protein complex (a complex of two or more proteins that may include other nonprotein molecules).
Evidence
1:
Inferred from Physical InteractionIntAct
Che-1 is a RNA polymerase II-binding protein involved in the transcription of E2F target genes and induction of cell proliferation. Here we show that Che-1 contributes to DNA damage response and that its depletion sensitizes cells to anticancer agents. The checkpoint kinases ATM/ATR and Chk2 interact with Che-1 and promote its phosphorylation and accumulation in response to DNA damage. These Che-1 modifications induce a specific recruitment of Che-1 on the TP53 and p21 promoters. Interestingly, it has a profound effect on the basal expression of p53, which is preserved following DNA damage. Notably, Che-1 contributes to the maintenance of the G2/M checkpoint induced by DNA damage. These findings identify a mechanism by which checkpoint kinases regulate responses to DNA damage.
Evidence
2:
Inferred from Physical InteractionUniProtKB
hRPB11 is a core subunit of RNA polymerase II (pol II) specifically down-regulated on doxorubicin (dox) treatment. Levels of this protein profoundly affect cell differentiation, cell proliferation, and tumorigenicity in vivo. Here we describe Che-1, a novel human protein that interacts with hRPB11. Che-1 possesses a domain of high homology with Escherichia coli RNA polymerase final sigma-factor 70 and SV40 large T antigen. In addition, we report that Che-1 interacts with the retinoblastoma susceptibility gene (Rb) by two distinct domains. Functionally, we demonstrate that Che-1 represses the growth suppression function of Rb, counteracting the inhibitory action of Rb on the trans-activation function of E2F1. These results identify a novel protein that binds Rb and the core of pol II, and suggest that Che-1 may be part of transcription regulatory complex.
Interacting selectively and non-covalently with a specific DNA sequence in order to modulate transcription. The transcription factor may or may not also interact selectively with a protein or macromolecular complex.
Dlk, also known as ZIP kinase, is a serine/threonine kinase that is tightly associated with nuclear structures. Under certain conditions, which require cytoplasmic localization, Dlk can induce apoptosis. In search for interaction partners that might serve as regulators or targets of this kinase we identified apoptosis antagonizing transcription factor (AATF), a nuclear phosphoprotein of 523 amino acids. The 1.8 kb mRNA seems to be ubiquitously expressed. AATF contains an extremely acidic domain and a putative leucine zipper characteristic of transcription factors. Indeed, a Gal4-BD-AATF fusion protein exhibited strong transactivation activity. Interestingly, AATF interfered with Dlk-induced apoptosis.
Interacting selectively and non-covalently with tau protein. tau is a microtubule-associated protein, implicated in Alzheimer's disease, Down Syndrome and ALS.
The first few specialized divisions of an activated animal egg.
IEAOrtholog Compara
Negative regulation of amyloid precursor protein biosynthetic processdefinition[GO:0042985]‹silver
Any process that stops, prevents, or reduces the frequency, rate or extent of the chemical reactions and pathways resulting in the formation of amyloid precursor protein (APP), the precursor of beta-amyloid.
Extensive loss of neurons and synapses in vulnerable regions of the brain is one of the most important pathological features of Alzheimer's disease (AD). Increased oxidative stress has been shown to contribute to the neurodegenerative process in AD. Aggregation of amyloid beta-peptide (Abeta) in amyloid plaques is one of the defining features of Alzheimer's disease. Indeed, Abeta has been shown to induce oxidative stress and apoptosis in many in vivo and in vitro models of AD. We now report that AATF (apoptosis-antagonizing transcription factor), a leucine zipper protein initially identified as an interaction partner of DAP like kinase (Dlk, a member of the pro-apoptotic Death-Associated Protein kinase family), is expressed in cortical neurons and in neural PC12 cells. Abeta induces alterations in AATF expression in cortical neurons. Inhibition of AATF induction sensitizes neurons to Abeta toxicity. Overexpression of AATF suppressed superoxide production, inhibited peroxynitrite formation and membrane lipid peroxidation, and protected against Abeta-induced apoptosis in PC12 cells. These results suggest that AATF is a novel neuroprotective factor and it may protect against Abeta-induced apoptosis through its effects on suppressing the production of reactive oxygen species (ROS). AATF may therefore represent a potential candidate for therapeutic intervention of neurodegeneration in both sporadic and familial forms of AD.
Extensive loss of neurons and synapses in vulnerable regions of the brain is one of the most important pathological features of Alzheimer's disease (AD). Increased oxidative stress has been shown to contribute to the neurodegenerative process in AD. Aggregation of amyloid beta-peptide (Abeta) in amyloid plaques is one of the defining features of Alzheimer's disease. Indeed, Abeta has been shown to induce oxidative stress and apoptosis in many in vivo and in vitro models of AD. We now report that AATF (apoptosis-antagonizing transcription factor), a leucine zipper protein initially identified as an interaction partner of DAP like kinase (Dlk, a member of the pro-apoptotic Death-Associated Protein kinase family), is expressed in cortical neurons and in neural PC12 cells. Abeta induces alterations in AATF expression in cortical neurons. Inhibition of AATF induction sensitizes neurons to Abeta toxicity. Overexpression of AATF suppressed superoxide production, inhibited peroxynitrite formation and membrane lipid peroxidation, and protected against Abeta-induced apoptosis in PC12 cells. These results suggest that AATF is a novel neuroprotective factor and it may protect against Abeta-induced apoptosis through its effects on suppressing the production of reactive oxygen species (ROS). AATF may therefore represent a potential candidate for therapeutic intervention of neurodegeneration in both sporadic and familial forms of AD.
Extensive loss of neurons and synapses in vulnerable regions of the brain is one of the most important pathological features of Alzheimer's disease (AD). Increased oxidative stress has been shown to contribute to the neurodegenerative process in AD. Aggregation of amyloid beta-peptide (Abeta) in amyloid plaques is one of the defining features of Alzheimer's disease. Indeed, Abeta has been shown to induce oxidative stress and apoptosis in many in vivo and in vitro models of AD. We now report that AATF (apoptosis-antagonizing transcription factor), a leucine zipper protein initially identified as an interaction partner of DAP like kinase (Dlk, a member of the pro-apoptotic Death-Associated Protein kinase family), is expressed in cortical neurons and in neural PC12 cells. Abeta induces alterations in AATF expression in cortical neurons. Inhibition of AATF induction sensitizes neurons to Abeta toxicity. Overexpression of AATF suppressed superoxide production, inhibited peroxynitrite formation and membrane lipid peroxidation, and protected against Abeta-induced apoptosis in PC12 cells. These results suggest that AATF is a novel neuroprotective factor and it may protect against Abeta-induced apoptosis through its effects on suppressing the production of reactive oxygen species (ROS). AATF may therefore represent a potential candidate for therapeutic intervention of neurodegeneration in both sporadic and familial forms of AD.
X-linked inhibitor of apoptosis protein (XIAP) is a member of the inhibitor of apoptosis proteins family that selectively binds and inhibits caspase-3, -7 and -9. As such, XIAP is an extremely potent suppressor of apoptosis and an attractive target for cancer treatment. Che-1 is an antiapoptotic agent involved in the control of gene transcription and cell proliferation. Recently, we showed that the checkpoint kinases ATM/ATR and checkpoint kinase 2 physically and functionally interact with Che-1 and promote its phosphorylation and accumulation in response to DNA damage. These Che-1 modifications induce transcription of p53, and Che-1 depletion strongly sensitizes tumor cells to anticancer drugs. Here we show that Che-1 activates XIAP expression in response to DNA damage. This effect is mediated by Che-1 phosphorylation and requires NF-kappaB. Notably, we found that XIAP expression is necessary for antiapoptotic activity of Che-1 and that in vivo downregulation of Che-1 by small interference RNA strongly enhanced the cytotoxicity of anticancer drugs.
Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a stimulus indicating damage to its DNA from environmental insults or errors during metabolism.
Evidence
1:
Inferred from Expression PatternUniProtKB
X-linked inhibitor of apoptosis protein (XIAP) is a member of the inhibitor of apoptosis proteins family that selectively binds and inhibits caspase-3, -7 and -9. As such, XIAP is an extremely potent suppressor of apoptosis and an attractive target for cancer treatment. Che-1 is an antiapoptotic agent involved in the control of gene transcription and cell proliferation. Recently, we showed that the checkpoint kinases ATM/ATR and checkpoint kinase 2 physically and functionally interact with Che-1 and promote its phosphorylation and accumulation in response to DNA damage. These Che-1 modifications induce transcription of p53, and Che-1 depletion strongly sensitizes tumor cells to anticancer drugs. Here we show that Che-1 activates XIAP expression in response to DNA damage. This effect is mediated by Che-1 phosphorylation and requires NF-kappaB. Notably, we found that XIAP expression is necessary for antiapoptotic activity of Che-1 and that in vivo downregulation of Che-1 by small interference RNA strongly enhanced the cytotoxicity of anticancer drugs.
A cellular process that results in the biosynthesis of constituent macromolecules, assembly, and arrangement of constituent parts of ribosome subunits; includes transport to the sites of protein synthesis.
IEAOrtholog Compara
Pathways
According to Reactome, this protein belongs to the following pathway:
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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