PATZ1 is a DNA damage responsive transcription factor that inhibits p53 function [with and without doxorubicin treatment]
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE71558 | GEO | 2015/07/30
SECONDARY ACCESSION(S): PRJNA291506
REPOSITORIES: GEO
Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2015-07-30 | E-GEOD-71558 | biostudies-arrayexpress
Project description:Insults to cellular health cause p53 protein accumulation and loss of p53 function leads to tumorigenesis. Thus, p53 has to be tightly controlled. Here we report that the BTB/POZ domain transcription factor PATZ1 (MAZR), previously known for its transcriptional suppressor functions in T lymphocytes, is a crucial regulator of p53. The novel inhibitory role of PATZ1 on the p53 protein marks it as a proto-oncogene. PATZ1 deficient cells have reduced proliferative capacity which we assess by RNASeq and real time cell growth rate analysis. PATZ1 modifies the expression of p53 target genes associated with cell proliferation gene ontology terms. Moreover, PATZ1 regulates several genes involved in cellular adhesion and morphogenesis. Significantly, treatment with the DNA damage inducing drug doxorubicin results in the loss of the PATZ1 transcription factor, as p53 accumulates. We find that PATZ1 binds to p53 and inhibits p53 dependent transcription activation. We examine the mechanism of this functional inhibitory interaction and demonstrate that PATZ1 excludes p53 from DNA binding. This study documents PATZ1 as a novel player in the p53 pathway.
2017-07-29 | GSE71529 | GEO
Project description:Insults to cellular health cause p53 protein accumulation, and loss of p53 function leads to tumorigenesis. Thus, p53 has to be tightly controlled. Here we report that the BTB/POZ domain transcription factor PATZ1 (MAZR), previously known for its transcriptional suppressor functions in T lymphocytes, is a crucial regulator of p53. The novel role of PATZ1 as an inhibitor of the p53 protein marks its gene as a proto-oncogene. PATZ1-deficient cells have reduced proliferative capacity, which we assessed by transcriptome sequencing (RNA-Seq) and real-time cell growth rate analysis. PATZ1 modifies the expression of p53 target genes associated with cell proliferation gene ontology terms. Moreover, PATZ1 regulates several genes involved in cellular adhesion and morphogenesis. Significantly, treatment with the DNA damage-inducing drug doxorubicin results in the loss of the PATZ1 transcription factor as p53 accumulates. We find that PATZ1 binds to p53 and inhibits p53-dependent transcription activation. We examine the mechanism of this functional inhibitory interaction and demonstrate that PATZ1 excludes p53 from DNA binding. This study documents PATZ1 as a novel player in the p53 pathway.
| S-EPMC4405645 | biostudies-literature
Project description:Insults to cellular health cause p53 protein accumulation and loss of p53 function leads to tumorigenesis. Thus, p53 has to be tightly controlled. Here we report that the BTB/POZ domain transcription factor PATZ1 (MAZR), previously known for its transcriptional suppressor functions in T lymphocytes, is a crucial regulator of p53. The novel inhibitory role of PATZ1 on the p53 protein marks it as a proto-oncogene. PATZ1 deficient cells have reduced proliferative capacity which we assess by RNASeq and real time cell growth rate analysis. PATZ1 modifies the expression of p53 target genes associated with cell proliferation gene ontology terms. Moreover, PATZ1 regulates several genes involved in cellular adhesion and morphogenesis. Significantly, treatment with the DNA damage inducing drug doxorubicin results in the loss of the PATZ1 transcription factor, as p53 accumulates. We find that PATZ1 binds to p53 and inhibits p53 dependent transcription activation. We examine the mechanism of this functional inhibitory interaction and demonstrate that PATZ1 excludes p53 from DNA binding. This study documents PATZ1 as a novel player in the p53 pathway. RNA-seq was used to define differentially expressed genes in wild-type and PATZ1-/- MEFs. Each sample was represented in triplicate.
2015-03-27 | E-GEOD-65864 | biostudies-arrayexpress
Project description:Insults to cellular health cause p53 protein accumulation and loss of p53 function leads to tumorigenesis. Thus, p53 has to be tightly controlled. Here we report that the BTB/POZ domain transcription factor PATZ1 (MAZR), previously known for its transcriptional suppressor functions in T lymphocytes, is a crucial regulator of p53. The novel inhibitory role of PATZ1 on the p53 protein marks it as a proto-oncogene. PATZ1 deficient cells have reduced proliferative capacity which we assess by RNASeq and real time cell growth rate analysis. PATZ1 modifies the expression of p53 target genes associated with cell proliferation gene ontology terms. Moreover, PATZ1 regulates several genes involved in cellular adhesion and morphogenesis. Significantly, treatment with the DNA damage inducing drug doxorubicin results in the loss of the PATZ1 transcription factor, as p53 accumulates. We find that PATZ1 binds to p53 and inhibits p53 dependent transcription activation. We examine the mechanism of this functional inhibitory interaction and demonstrate that PATZ1 excludes p53 from DNA binding. This study documents PATZ1 as a novel player in the p53 pathway.
2015-03-27 | GSE65864 | GEO
Project description:Liver cancer is the third most common cause of cancer death in the world. POZ/BTB and AT-hook-containing zinc finger protein 1 (PATZ1/MAZR) is a transcription factor associated with various cancers. However, the role of PATZ1 in cancer progression remains controversial largely due to lack of genome-wide studies. Here we report that PATZ1 regulates cell proliferation by directly regulating CDKN1B (p27) in hepatocellular carcinoma cells. Our PATZ1 ChIP-seq and gene expression microarray analyses revealed that PATZ1 is strongly related to cancer signatures and cellular proliferation. We further discovered that PATZ1 depletion led to an increased rate of colony formation, elevated Ki-67 expression and greater S phase entry. Importantly, the increased cancer cell proliferation was accompanied with suppressed expression of the cyclin-dependent kinase inhibitor CDKN1B. Consistently, we found that PATZ1 binds to the genomic loci flanking the transcriptional start site of CDKN1B and positively regulates its transcription. Notably, we demonstrated that PATZ1 is a p53 partner and p53 is essential for CDKN1B regulation. In conclusion, our study provides novel mechanistic insights into the inhibitory role of PATZ1 in liver cancer progression, thereby yielding a promising therapeutic intervention to alleviate tumor burden.
| S-EPMC7882738 | biostudies-literature
Project description:Circadian period proteins influence cell division and death by associating with checkpoint components, although their mode of regulation has not been firmly established. hPer2 forms a trimeric complex with hp53 and its negative regulator Mdm2. In unstressed cells, this association leads to increased hp53 stability by blocking Mdm2-dependent ubiquitination and transcription of hp53 target genes. Because of the relevance of hp53 in checkpoint signaling, we hypothesize that hPer2 association with hp53 acts as a regulatory module that influences hp53's downstream response to genotoxic stress. Unlike the trimeric complex, whose distribution was confined to the nuclear compartment, hPer2/hp53 was identified in both cytosol and nucleus. At the transcriptional level, a reporter containing the hp21(WAF1/CIP1) promoter, a target of hp53, remained inactive in cells expressing a stable form of the hPer2/hp53 complex even when treated with γ-radiation. Finally, we established that hPer2 directly acts on the hp53 node, as checkpoint components upstream of hp53 remained active in response to DNA damage. Quantitative transcriptional analyses of hp53 target genes demonstrated that unbound hp53 was absolutely required for activation of the DNA-damage response. Our results provide evidence of the mode by which the circadian tumor suppressor hPer2 modulates hp53 signaling in response to genotoxic stress.
| S-EPMC4294682 | biostudies-literature
Project description:Vascular cell senescence, induced by the DNA damage response or inflammatory stress, contributes to age-associated vascular disease. Using complementary DNA microarray technology, we found that the level of POZ/BTB and AT-hook-containing zinc finger protein 1 (PATZ1) is downregulated during endothelial cell (EC) senescence. PATZ1 may have an important role as a transcriptional repressor in chromatin remodeling and transcription regulation; however, the role of PATZ1 in EC senescence and vascular aging remains unidentified. Knockdown of PATZ1 in young cells accelerated premature EC senescence, which was confirmed by growth arrest, increased p53 protein level and senescence-associated β-galactosidase (SA-β-gal) activity, and repression of EC tube formation. In contrast, overexpression of PATZ1 in senescent cells reversed senescent phenotypes. Cellular senescence induced by PATZ1 knockdown in young cells was rescued by knockdown of p53, but not by knockdown of p16(INK4a). PATZ1 knockdown increased ROS levels, and pretreatment with N-acetylcysteine abolished EC senescence induced by PATZ1 knockdown. Notably, PATZ1 immunoreactivity was lower in ECs of atherosclerotic tissues than those of normal arteries in LDLR(-/-) mice, and immunoreactivity also decreased in ECs of old human arteries. These results suggest that PATZ1 may have an important role in the regulation of EC senescence through an ROS-mediated p53-dependent pathway and contribute to vascular diseases associated with aging.
| S-EPMC3307983 | biostudies-literature
Project description:We previously demonstrated that Bim is the main BH3-only protein replacing Bak/Bax from Bcl-xl to activate apoptosis in a p53-independent manner in response to doxorubicin in prostate cancer. However, the comparison of doxorubicin treatment between LNCaP cells carrying p53-wild type and PC3 cells carrying p53-null suggested that p53 might be essential for maximizing apoptosis. Inhibition of ATM did not affect doxorubicin-induced apoptosis. Overexpression of p53 did not affect ABT-263-induced apoptosis and nevertheless, the combination of doxorubicin with ABT-263 induced higher apoptotic responses than did doxorubicin or ABT-263 alone. These results advocated that doxorubicin-induced DNA damage controls p53 function for intensifying apoptosis. Indeed, overexpression of p53 only enhanced apoptosis under conditions of severe DNA damage induced by high concentrations of doxorubicin in LNCaP cells. Immunofluorescence staining showed vague γH2AX foci and enlarged nuclei in LNCaP cells in response to high concentrations of doxorubicin, en route to apoptosis. In addition, our results revealed that the apoptosis in response to DNA replication stress induced by CFS-1686, a catalytic inhibitor of topoisomerase, is p53-independent. Interestingly, the combination of doxorubicin with CFS-1686 generated DNA damage and replication stress simultaneously, resulting in a synergistic apoptotic effect in prostate cancer cells. Thus, we concluded that p53 is a sensor for enhanced apoptosis in response to DNA damage stress, not DNA replication stress, at least in prostate cancer.
| S-EPMC6226221 | biostudies-literature
Project description:DNAJB9 is a recently isolated member of the molecular chaperone gene family, whose precise function is largely unknown. In the present study, we have identified DNAJB9 as an inducible gene of the tumor suppressor p53. DNAJB9 expression was induced by p53 or genotoxic stress in a p53-dependent manner, which was mediated by the Ras/Raf/ERK pathway. In addition, depletion of DNAJB9 by using siRNAs greatly increased genotoxic stress/p53-induced apoptosis, suggesting that DNAJB9 inhibits the pro-apoptotic function of p53. We also found that DNAJB9 physically interacts with p53 through its J domain, through which it inhibits the pro-apoptotic function of p53. Moreover, DNAJB9 colocalized with p53 in both cytoplasm and nucleus under genotoxic conditions. Together, these results demonstrate that DNAJB9 is a downstream target of p53 that belongs to the group of negative feedback regulators of p53.
| S-EPMC4262772 | biostudies-literature