Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ecteinascidin 743 (ET-743; Yondelis, Trabectedin) is a marine anticancer agent that induces long-lasting objective remissions and tumor control in a subset of patients with pretreated/resistant soft-tissue sarcoma. Drug-induced tumor control is achievable in 22% of such patients, but there is no clear indication of the molecular features correlated with clinical sensitivity/resistance to ET-743. Nine low-passage, soft-tissue sarcoma cell lines, explanted from chemo-naive patients with different patterns of sensitivity, have been profiled with a cDNA microarray containing 6,700 cancer-related genes. The molecular signature of these cell lines was analyzed at baseline and at four different times after ET-743 exposure. The association of levels of TP53 mutation and TP73 expression with ET-743 sensitivity and cell cycle kinetics after treatment was also analyzed. Gene expression profile analysis revealed up-regulation of 86 genes and down-regulation of 244 genes in response to ET-743. The ET-743 gene expression signature identified a group of genes related with cell cycle control, stress, and DNA-damage response (JUNB, ATF3, CS-1, SAT, GADD45B, and ID2) that were up-regulated in all the cell lines studied. The transcriptional signature 72 hours after ET-743 administration, associated with ET-743 sensitivity, showed a more efficient induction of genes involved in DNA-damage response and apoptosis, such as RAD17, BRCA1, PAR4, CDKN1A, and P53DINP1, in the sensitive cell line group. The transcriptional signature described here may lead to the identification of ET-743 downstream mediators and transcription regulators and the proposal of strategies by which ET-743-sensitive tumors may be identified.
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PMID:Transcriptional signature of Ecteinascidin 743 (Yondelis, Trabectedin) in human sarcoma cells explanted from chemo-naive patients. 1589 46

Restin, a member of melanoma-associated antigen superfamily gene, was first cloned from differentiated leukemia cell induced by all trans-retinoic acid, and was able to inhibit cell proliferation, but the molecular mechanism was not clear. Since Restin was localized in cell nucleus, and its homolog member, Necdin (neuronal growth suppressor factor), could interact with transcription factors p53 and E2F1, we proposed that Restin might also function as Necdin through interacting with some transcription factors. In this study, transcription factors p53, AP1, ATFs and E2Fs were cloned and used in the mammalian two-hybrid system to identify their interaction with Restin. The results showed that only ATF3 had a strong interaction with Restin. It is interesting to know that ATF3 was an important transcription factor for G1 cell cycle initiation in physiological stress response. It was possible that the inhibition of cell proliferation by Restin might be related with the inhibition of ATF3 activity.
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PMID:Interaction of restin with transcription factors. 1609 58

Male F344 rats were intravenously treated with 6 mg/kg cycloheximide (CHX), and microarray analysis was conducted on their livers 1, 2 and 6h after the CHX treatment. The histopathological examination and serum chemistry results indicated a mild hepatic cell death 2 and 6h after the CHX treatment, respectively. Multi-focal hepatocellular necrosis with slight neutrophil infiltration was observed 6h after the CHX treatment. The TUNEL staining results showed that the number of apoptotic hepatocytes was the highest 2h after the CHX treatment. Dramatic increases in the mRNA levels of ATF3 and CHOP genes, both of which were reported to play roles in the ER stress-mediated apoptosis pathway, were observed from 1h after the CHX treatment. In addition, increase of GADD45, p21 and p53 mRNA levels also suggested a time course-related stimulation of hepatocellular apoptotic signals. These results suggest that the hepatocyte apoptosis induced by the CHX treatment is triggered by ER stress. The hepatic mRNA levels of proinflammatory genes, such as TNFalpha, IL-1alpha and beta, were also increased 1 and 2h after the CHX treatment, supposedly mediated by the activated Kupffer cells engulfing the apoptotic hepatocytes.
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PMID:Molecular mechanism investigation of cycloheximide-induced hepatocyte apoptosis in rat livers by morphological and microarray analysis. 1636 79

ATF3 is a member of the ATF/CREB family of transcription factors involved in the cellular response to a large variety of stresses including DNA damage. However, neither the signaling leading to nor the biological significance of its induction upon stress is well understood. Although it is generally believed that ATF3 exerts its function in the stress response by regulating transcription, to date, only a limited number of target genes have been identified. We recently reported that ATF3 interacts with the tumor suppressor p53 to increase its stability in the genotoxic response. While providing the cell a general means of responding to diverse adverse environment cues, this mechanism confers ATF3 with an ability to promote tumor suppressor functions. Conversely, dysfunction of ATF3 impairs the p53-mediated cellular response to DNA damage, allowing cells to be readily transformed by oncogenes. Consistent with this notion is the observation of downregulated ATF3 expression in most human cancers. Therefore, our findings indicate that ATF3 intersects with p53-associated pathways ensuring genomic integrity. The ability of ATF3 to stabilize p53-induced pathways thus represents a means of effectively countering DNA damage caused by environmental insult the latter leading to oncogene activation and ultimately malignant transformation.
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PMID:ATF3 regulates the stability of p53: a link to cancer. 1662 10

Gemcitabine is a nucleoside analog with clinical relevance in the treatment of several solid tumors, including breast carcinoma. In spite of its cytotoxic effect, clinical efficacy is impaired by the development of resistance. We performed gene expression analysis to shed light into the molecular mechanism of action of this drug in two breast cancer cell lines. Activation of genes related with cell cycle, cell growth and apoptosis (BNIP3L, CCNG2, DDIT4, TGFB2, TP53BP1, TP53INP1, and VEGF) was the main finding in the p53-wild type cell line MCF7, while the p53-non-functional cell line MDA-MB-231 was characterized by the regulation of NF-kappaB target genes (BIRC3, CXCL1/GRO1, IRAK2, TNF, TNFAIP and TRAF1). Genes consistently induced (ATF3, CCNG2, CDKN1A, EGR1, INSIG1, and MAF) or repressed (CCND1 and VGF) in both cell lines, were also found after gemcitabine treatment. In addition, MDA-MB-231 cells showed a higher basal and induced NF-kappaB transcriptional activity after treatment with gemcitabine. In comparison with gemcitabine, gene expression after 5-fluorouracil treatment showed essentially different profiles in both cell lines. This, in spite of using equitoxic concentrations producing similar effects on cell cycle. NF-kappaB transcriptional activity in MDA-MB-231 cells was dependent on IkappaB-alpha phosphorylation, as shown by functional experiments using the specific inhibitor BAY11-7082. Moreover, immunohistochemical analysis of clinical samples of breast carcinoma further validated the induction of NF-kappaB expression and IkappaB down-regulation upon neoadjuvant gemcitabine treatment. Thus, gene expression patterns, in vitro functional studies and analysis of tissue samples are in agreement with a role for NF-kappaB pathway in gemcitabine response. Together with the reported role for NF-kappaB in the induction of resistance to chemotherapy, our data gives support to clinical strategies combining gemcitabine with NF-kappaB inhibitors in breast cancer.
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PMID:Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. 1703 68

ATF3 is a highly conserved eukaryotic transcription factor that is ubiquitously upregulated transcriptionally during cellular responses to a variety of stresses, in particular DNA damage. However, the role of ATF3 in the DNA damage response is unclear. Transgenic mice that overexpress human ATF3 in basal epithelial cells under the control of the bovine keratin 5 (K5) promoter were constructed and characterized for epidermal alterations. Strong, nuclear expression of the exogenous ATF3 protein was seen in basal cells of the epidermis, hair follicles, and oral mucosa. Hyperplastic changes in the K5-expressing, outer root sheath (ORS) cells of the hair follicle were observed in young mice, resulting in multiple layers of ORS cells in the mature follicle and large aberrantly shaped follicles. Mild hyperplasia of the interfollicular epidermis was also noted, increasing with age. However, no epidermal tumors were identified in BK5.ATF3 mice observed for 16 mo. At 16 mo of age, most transgenic mice exhibited multi-focal areas of hyperplasia and dysplasia in the oral mucosa, with cellular atypia and underlying acute inflammatory changes. Neoplastic lesions were also seen in the oral cavity of BK5.ATF3 mice, including oral squamous cell carcinoma (60% incidence) and basal cell tumors with follicular differentiation (70% incidence), but not in non-transgenic FVB/N littermates. Heterogeneous nuclear expression (or stabilization) of p53 protein was seen in some oral dysplasias, with a patchy distribution primarily in the least differentiated layers of the lesions. This represents the first indication that ATF3 may have oncogenic properties in epithelial cells.
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PMID:Epidermal hyperplasia and oral carcinoma in mice overexpressing the transcription factor ATF3 in basal epithelial cells. 1729 36

Berberine is known to possess a wide variety of pharmacological activities, including pro-apoptotic activity. However, its molecular targets are not elucidated at present. NAG-1 and ATF3 are induced by several dietary compounds associated with pro-apoptotic activity. Berberine induces cell growth arrest, apoptosis, NAG-1, and ATF3 in human colorectal cancer cells. ATF3 induction by berberine is mediated in a p53-dependent manner, whereas NAG-1 induction by berberine is mediated by multiple signaling pathways. Our results suggest that berberine facilitates apoptosis and that NAG-1 and ATF3 expression plays an important role in berberine-induced apoptosis.
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PMID:Berberine, a natural isoquinoline alkaloid, induces NAG-1 and ATF3 expression in human colorectal cancer cells. 1796 72

JNK and ERK MAP kinases regulate cellular responses to genotoxic stress in a cell type and cell context-dependent manner. However, the factors that determine and execute JNK- and ERK-controlled stress responses are only partly known. In this study, we investigate the roles of the AP-1 components ATF3 and Fra1 in JNK- and ERK-dependent cell cycle arrest and apoptosis. We show that the anti-cancer drug cisplatin or UV light activates both JNK and ERK in human glioblastoma cells lacking functional p53. Inhibition experiments of JNK or ERK activities revealed that the ERK pathway strongly promotes cisplatin- and UV-induced apoptosis in these glioblastoma cells. Furthermore, JNK but not ERK is required for ATF3 induction, and both ERK and JNK are necessary for post-transcriptional induction of Fra1 in response to cisplatin or UV. Knock-down of ATF3 and Fra1 results in increased and decreased cisplatin-induced apoptosis, respectively, indicating that ATF3 is an anti-apoptotic JNK effector and Fra1 is a pro-apoptotic ERK/JNK effector. Knock-down experiments also revealed that ATF3 and Fra1, respectively, enhance and reduce S-phase arrest through differential modulation of the Chk1-Cdk2 pathway. Thus, we identify novel reciprocal functions of ATF3 and Fra1 in JNK- and ERK-dependent DNA damage responses.
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PMID:ATF3 and Fra1 have opposite functions in JNK- and ERK-dependent DNA damage responses. 1824 59

Glioblastomas (GBMs) are resistant to apoptosis but less so to autophagy; a fact that may at least partly explain the therapeutic benefits of the pro-autophagic drug temozolomide in the treatment of GBM patients. Galectin-1 (Gal1) whose expression is stimulated by hypoxia is a potent modulator of GBM cell migration and a pro-angiogenic molecule. Hypoxia is also known to confer cancer cells with resistance to chemotherapy and radiotherapy and to modulate the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress. The present study investigates whether decreasing Gal1 expression (by means of a siRNA approach) in human Hs683 GBM cells increases their sensitivity to pro-autophagic or pro-apoptotic drugs. The data reveal that temozolomide, the standard treatment for glioma patients, increases Gal1 expression in Hs683 cells both in vitro and in vivo. However, reducing Gal1 expression in these cells by siRNA increases the anti-tumor effects of various chemotherapeutic agents, in particular temozolomide both in vitro and in vivo. This decrease in Gal1 expression in Hs683 cells does not induce apoptotic or autophagic features, but is found to modulate p53 transcriptional activity and decrease p53-targeted gene expression including DDIT3/GADD153/CHOP, DUSP5 ATF3 and GADD45A. The decrease in Gal1 expression also impairs the expression levels of seven other genes implicated in chemoresistance: ORP150, HERP, GRP78/Bip, TRA1, BNIP3L, GADD45B and CYR61, some of which are located in the ER and whose expression is also known to be modified by hypoxia. This novel facet of Gal1 involvement in glioblastoma biology may be amenable to therapeutic manipulation.
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PMID:Evidence of galectin-1 involvement in glioma chemoresistance. 1831 12

Eukaryotic cells respond to DNA damage and stalled replication forks by activating signaling pathways that promote cell cycle arrest and DNA repair. A systematic screening of the protein kinase small interfering RNA library reveals that Chk1 and ataxia telangiectasia-mutated (ATM) and Rad3-related (ATR) are the main kinases responsible for intra-S-phase checkpoint upon topoisomerase I inhibitor camptothecin-induced DNA damage. It is well known that ATR-Chk1-mediated protein degradation of Cdc25A protein phosphatase is a crucial mechanism conferring this checkpoint activation. Here we describe another mechanism underlying Cdc25A down-regulation in response to DNA damage that occurs at the transcriptional level. We show that activation of tumor suppressor p53 by DNA damage results in inhibition of Cdc25A transcription as a result of activation of transcriptional repressor ATF3 that directly binds to the Cdc25A promoter. In cells deficient in both Chk1 and p53, Cdc25A down-regulation upon camptothecin-induced DNA damage is completely abolished, leading to severe defects in cell cycle checkpoints and remarkable cell death in mitosis. Our findings reveal two independent mechanisms acting in concert in regulation of Cdc25A in DNA damage response. Although Chk1 affects Cdc25A via rapid phosphorylation and protein turnover, inhibition of Cdc25A transcription by p53-ATF3 is required for the maintenance of cell cycle arrest.
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PMID:Dual regulation of Cdc25A by Chk1 and p53-ATF3 in DNA replication checkpoint control. 1906 Mar 37


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