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)

Methionine deprivation imposes a metabolic stress, termed methionine stress, that inhibits mitosis and induces cell cycle arrest and apoptosis. The methionine-dependent central nervous system tumor cell lines DAOY (medulloblastoma), SWB61 (anaplastic oligodendroglioma), SWB40 (anaplastic astrocytoma), and SWB39 (glioblastoma multiforme) were compared with methionine-stress resistant SWB77 (glioblastoma multiforme). The cDNA-oligoarray analysis and reverse transcription-PCR verification indicated common changes in gene expression in methionine-dependent cell lines to include up-regulation/induction of cyclin D1, mitotic arrest deficient (MAD)1, p21, growth arrest and DNA-damage-inducible (GADD)45 alpha, GADD45 gamma, GADD34, breast cancer (BRCA)1, 14-3-3sigma, B-cell CLL/lymphoma (BCL)1, transforming growth factor (TGF)-beta, TGF-beta-induced early response (TIEG), SMAD5, SMAD7, SMAD2, insulin-like growth factor binding protein (IGFBP7), IGF-R2, vascular endothelial growth factor (VEGF), TNF-related apoptosis-inducing ligand (TRAIL), TNF-alpha converting enzyme (TACE), TRAIL receptor (TRAIL-R)2, TNFR-related death receptor (DR)6, TRAF interacting protein (I-TRAF), IL-6, MDA7, IL-1B convertase (ICE)-gamma, delta and epsilon, IRF1, IRF5, IRF7, interferon (IFN)-gamma and receptor components, ISG15, p65-NF-kappaB, JUN-B, positive cofactor (PC)4, C/ERB-beta, inositol triphosphate receptor I, and methionine adenosyltransferase II. On the other hand, cyclins A1, A2, B1 and B2, cell division cycle (CDC)2 and its kinase, CDC25 A and B, budding uninhibited by benzimidazoles (BUB)1 and 3, MAD2, CDC28 protein kinase (CKS)1 and 2, neuroepithelial cell transforming gene (NET)1, activator of S-phase kinase (ASK), CDC14B phosphatase, BCL2, TGF-beta activated kinase (TAK)1, TAB1, c-FOS, DNA topoisomerase II, DNA polymerase alpha, dihydrofolate reductase, thymidine kinase, stathmin, and MAP4 were down-regulated. In the methionine stress-resistant SWB77, only 20% of the above genes were affected, and then only to a lesser extent. In addition, some of the changes observed in SWB77 were opposite to those seen in methionine-dependent tumors, including expression of p21, TRAIL-R2, and TIEG. Despite similarities, differences between methionine-dependent tumors were substantial, especially in regard to regulation of cytokine expression. Western blot analysis confirmed that methionine stress caused the following: (a) a marked increase of GADD45alpha and gamma in the wt-p53 cell lines SWB61 and 40; (b) an increase in GADD34 and p21 protein in all of the methionine-dependent lines; and (c) the induction of MDA7 and phospho-p38 in DAOY and SWB39, consistent with marked transcriptional activation of the former under methionine stress. It was additionally shown that methionine stress down-regulated the highly active phosphatidylinositol 3'-kinase pathway by reducing AKT phosphorylation, especially in DAOY and SWB77, and also reduced the levels of retinoblastoma (Rb) and pRb (P-ser780, P-ser795, and P-ser807/811), resulting in a shift in favor of unphosphorylated species in all of the methionine-dependent lines. Immunohistochemical analysis showed marked inhibition of nuclear translocation of nuclear factor kappaB under methionine stress in methionine-dependent lines. In this study we show for the first time that methionine stress mobilizes several defined cell cycle checkpoints and proapoptotic pathways while coordinately inhibiting prosurvival mechanisms in central nervous system tumors. It is clear that methionine stress-induced cytotoxicity is not restricted by the p53 mutational status.
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PMID:Modulation of gene expression in human central nervous system tumors under methionine deprivation-induced stress. 1549 78

Genetically engineered mouse mammary cancer models have been used over the years as systems to study human breast cancer. However, much controversy exists on the utility of such models as valid equivalents to the human cancer condition. To perform an interspecies gene expression comparative study in breast cancer we used a mouse model that most closely resembles human breast carcinogenesis. This system relies on the transplant of p53 null mouse mammary epithelial cells into the cleared mammary fat pads of syngeneic hosts. Serial analysis of gene expression (SAGE) was used to obtain gene expression profiles of normal and tumor samples from this mouse mammary cancer model (>300,000 mouse mammary-specific tags). The resulting mouse data were compared with 25 of our human breast cancer SAGE libraries (>2.5 million human breast-specific tags). We observed significant similarities in the deregulation of specific genes and gene families when comparing mouse with human breast cancer SAGE data. A total of 72 transcripts were identified as commonly deregulated in both species. We observed a systematic and significant down-regulation in all of the tumors from both species of various cytokines, including CXCL1 (GRO1), LIF, interleukin 6, and CCL2. All of the mouse and most human mammary tumors also displayed decreased expression of genes known to inhibit cell proliferation, including NFKBIA (IKBalpha), GADD45B, and CDKN1A (p21); transcription-related genes such as CEBP, JUN, JUNB, and ELF1; and apoptosis-related transcripts such as IER3 and GADD34/PPP1R15A. Examples of overexpressed transcripts in tumors from both species include proliferation-related genes such as CCND1, CKS1B, and STMN1 (oncoprotein 18); and genes related to other functions such as SEPW1, SDFR1, DNCI2, and SP110. Importantly, abnormal expression of several of these genes has not been associated previously with breast cancer. The consistency of these observations was validated in independent mouse and human mammary cancer sets. This is the first interspecies comparison of mammary cancer gene expression profiles. The comparative analysis of mouse and human SAGE mammary cancer data validates this p53 null mouse tumor model as a useful system closely resembling human breast cancer development and progression. More importantly, these studies are allowing us to identify relevant biomarkers of potential use in human studies while leading to a better understanding of specific mechanisms of human breast carcinogenesis.
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PMID:From mice to humans: identification of commonly deregulated genes in mammary cancer via comparative SAGE studies. 1552 Jan 79

Increased amounts of reactive oxygen species (ROS) induce apoptosis in mammalian cells. PUMA (P53 up-regulated modulator of apoptosis), a mitochondrial proapoptotic BH3-only protein, induces rapid apoptosis through a Bax- and mitochondria-dependent pathway. However, the molecular basis of PUMA-induced apoptosis is largely not understood. Using a combination of biophysical and biochemical methods and PUMA-inducible colorectal cells, DLD-1.PUMA, we showed that (a) PUMA-induced apoptosis is dose and time dependent; (b) PUMA-induced apoptosis is directly associated with ROS generation; (c) diphenyleneiodonium chloride, a ROS blocker, or BAX-inhibiting peptide, a suppressor of BAX translocation, decreased ROS generation and apoptosis in DLD-1.PUMA cells; (d) overexpression of PUMA induced up-regulation (>1.34-fold) of peroxiredoxin 1 and down-regulation (by 25%) of stathmin through proteasome-mediated degradation; and (e) hydrogen peroxide down-regulated stathmin and disrupted the cellular microtubule network. Our findings indicate that PUMA induces apoptosis, in part, through the BAX-dependent generation of superoxide and hydrogen peroxide. ROS overproduction and oxidative stress induce proteome-wise alterations, such as stathmin degradation and disorganization of the cell microtubule network, in apoptotic cells.
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PMID:PUMA overexpression induces reactive oxygen species generation and proteasome-mediated stathmin degradation in colorectal cancer cells. 1575 58

Ischemia-reperfusion injury (IRI) in liver and other organs is manifested as an injury phase followed by recovery and resolution. Control of cell growth and proliferation is essential for recovery from the injury. We examined the expression of three related regulators of cell cycle progression in liver IRI: spermidine/spermine N-acetyltransferase (SSAT), p21 (a cyclin-dependent kinase inhibitor), and stathmin. Mice were subjected to hepatic IRI, and liver tissues were harvested at timed intervals. The expression of SSAT, the rate-limiting enzyme in the polyamine catabolic pathway, had increased fivefold 6 h after IRI and correlated with increased putrescine levels in the liver, consistent with increased SSAT enzymatic activity in IRI. The expression of p21, which is transactivated by p53, was undetectable in sham-operated animals but was heavily induced at 12 and 24 h of reperfusion and declined to undetectable baseline levels at 72 h of reperfusion. The interaction of the polyamine pathway with the p53-p21 pathway was shown in vitro, where activation of SSAT with polyamine analog or the addition of putrescine to cultured hepatocytes induced the expression of p53 and p21 and decreased cell viability. The expression of stathmin, which is under negative transcriptional regulation by p21 and controls cell proliferation and progression through mitosis, remained undetectable at 6, 12, and 24 h of reperfusion and was progressively and heavily induced at 48 and 72 h of reperfusion. Double-immunofluorescence labeling with antibodies against stathmin and PCNA, a marker of cell proliferation, demonstrated colocalization of stathmin and PCNA at 48 and 72 h of reperfusion in hepatocytes, indicating the initiation of cell proliferation. The distinct and sequential upregulation of SSAT, p21, and stathmin, along with biochemical activation of the polyamine catabolic pathway in IRI in vivo and the demonstration of p53-p21 upregulation by SSAT and putrescine in vitro, points to the important role of regulators of cell growth and cell cycle progression in the pathophysiology and/or recovery in liver IRI. The data further suggest that SSAT may play a role in the initiation of injury, whereas p21 and stathmin may be involved in the resolution and recovery after liver IRI.
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PMID:Distinct and sequential upregulation of genes regulating cell growth and cell cycle progression during hepatic ischemia-reperfusion injury. 1588 50

Copper toxicity associated with Wilson's disease is known to cause neuronal damage and death in the basal ganglia and frontal cortex leading to Parkinson-like symptoms and cognitive deficits. Our previous work in cultured human NTERA-2-N neurons showed that copper-induced neuronal apoptosis is dependent on the induction and nuclear translocation of the tumor suppressor protein, p53. Because p53 acts as a DNA-binding transcription factor, this work used an oligonucleotide array to identify p53 target genes that are differentially regulated in copper-loaded neurons. Arrays representing 145 human genes expressed downstream of p53 were hybridized with labeled mRNA from control and copper-treated neurons. Differentially regulated mRNAs included those involved in the regulation of the cell cycle, cytoprotective mechanisms, and apoptotic mechanisms. Transfection of cells with a dominant-negative p53 construct enabled us to determine which molecular events were dependent on p53 expression. Copper treatment resulted in the upregulation of p21, reprimo, stathmin, and Tp53INP1, all known to participate in cell cycle arrest. Protective mechanisms included the upregulation of stat-3, and the heat-shock proteins, heat-shock protein (Hsp) 70 and Hsp 27. Both p53-dependent and -independent mechanisms leading to apoptosis were identified including insulin-like growth factor binding protein-6, glutathione peroxidase, bcl-2, RB-1, PUMA, and several members of the redox active PIG family of proteins. Thus it appears that following copper-mediated neuronal DNA damage, the regulation of a variety of pro- and antiapoptotic genes are responsible for determining neuronal fate.
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PMID:Expression profiling of p53-target genes in copper-mediated neuronal apoptosis. 1639 88

Stathmin, a major microtubule-depolymerizing protein, is involved in cell cycle progression and cell motility. This study aimed to elucidate its role in the progression, early tumour recurrence (ETR), and prognosis of hepatocellular carcinoma (HCC). Stathmin mRNA was overexpressed in 88/156 (56%) resected, unifocal, primary HCCs, while p53 mutation was present in 72 (46%) and osteopontin mRNA overexpression in 79 (51%). Stathmin mRNA expression exhibited high concordance (93%) with protein expression in 107 cases examined by immunohistochemistry. Stathmin overexpression correlated with high alpha-fetoprotein (>200 ng/ml, p = 0.02), larger tumour size (>5 cm, p = 0.012), high tumour grade (p < 0.0002), high tumour stage (stage IIIA-IV) with vascular invasion and various degrees of intrahepatic metastasis (p < 1 x 10(-8)), ETR (p = 0.003), and lower 5-year survival (p = 0.0007). Stathmin protein expression was often more intense in the peripheral regions of tumour trabeculae, tumour borders, and portal vein tumour thrombi. Stathmin overexpression correlated with p53 mutation (p = 0.017) and osteopontin overexpression (p = 1 x 10(-8)), both of which were associated with vascular invasion (both p < 0.0001) and poorer prognosis (p < 0.0004 and p = 0.0004, respectively). Regardless of the status of p53 mutation or osteopontin expression, stathmin overexpression was associated with higher vascular invasion (all p < 0.0001). Approximately 90% of HCCs harbouring stathmin overexpression with concomitant p53 mutation or osteopontin overexpression exhibited vascular invasion, and hence the lowest 5-year survival, p = 0.00018 and p = 0.0009, respectively. However, we did not find that stathmin overexpression exerted prognostic impact independent of tumour stage. In conclusion, stathmin expression correlates with metastatic potential, is an important prognostic factor for HCC, and may serve as a useful marker to predict ETR.
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PMID:Stathmin overexpression cooperates with p53 mutation and osteopontin overexpression, and is associated with tumour progression, early recurrence, and poor prognosis in hepatocellular carcinoma. 1673 96

Cancers harboring dominant-negative p53 mutations are often aggressive and difficult to treat. Direct attempts to restore wild-type p53 function have produced little clinical benefit. We investigated whether targeting a p53-target gene could induce certain tumor-suppressor characteristics. We found that inhibition of stathmin, a microtubule regulator that can be transcriptionally repressed by wild-type p53, restored certain wild-type functions to cancer cells with mutant p53. Silencing of stathmin by small interfering RNA (siRNA) in mutant p53 cell lines lowered expression to that observed following activation of wild-type p53 by DNA damage in wild-type p53 cell lines. siRNA-induced repression of stathmin decreased cell proliferation, viability and clonogenicity in mutant p53 cell lines. Furthermore, knockdown of stathmin partially restored cell-cycle regulation and activation of apoptosis. Therefore, targeting stathmin, a gene product that is overexpressed in the presence of mutant p53, may represent a novel approach to treating cancers with aberrant p53 function.
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PMID:Silencing of stathmin induces tumor-suppressor function in breast cancer cell lines harboring mutant p53. 1690 2

Our laboratory discovered that p53 can regulate the sensitivity to cancer therapies by affecting three critical aspects of cancer pharmacology: 1). The expression of drug targets; 2). the access of drugs to intracellular targets; and the response to DNA damage. We review the effects of p53 on antimicrotubule drugs through transcriptional regulation of MAP4 and stathmin (Oncoprotein 18). These two p53-regulated proteins control microtubule dynamics, regulate the sensitivity to taxanes and vinca alkaloids by changing the polymerization dynamics of tubulin and affecting the binding of drugs to microtubules. We found that overexpression of MAP4 increased microtubule polymerization and increased taxane binding and sensitivity. Overexpression of stathmin, a microtubule destabilizer, virtually abolished cellular taxane binding and increased resistance by over 1000-fold. Yet, despite an increased binding of vinca alkaloids to stathmin transfectants, we did not observe increased drug sensitivity. This was explained, at least in part, by a delay in G2/M transit. We also discovered that p53 could regulate the expression of multidrug resistance protein-1 (MRP1), a member of the ABC family of transporters that mediates the sensitivity to vinca alkaloids and anthracyclines. We found that as prostate cancer progressed from low stage/low grade to high stage/high grade there was an increased expression of both MRP1 and staining for p53, a surrogate for p53 mutations. We went on to show that p53 regulated the expression of MRP1 and that this produced resistance to doxorubicin and vinblastine. We further demonstrated that MRP1 overexpression blocked the accumulation of flutamide and hydroxy-flutamide (the active metabolite) without affecting transport of dihydrotesterone, thereby blocking access of the anti-androgen but not the androgen to intracellular androgen receptors. Finally, we reviewed the effects of DNA damage on p53 expression and MAP4 repression as a means to increase the effectiveness of breast cancer treatment. These data demonstrated the possibility of individualizing treatment based on p53 status.
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PMID:The individualization of cancer therapy: the unexpected role of p53. 1852 66

Dysregulation of the plasminogen activation cascade is a prototypic feature in many malignant epithelial cancers. Principally, this is thought to occur through activation of overexpressed urokinase plasminogen activator (uPA) concomitant with binding to its high specificity cell surface receptor urokinase plasminogen activator receptor (uPAR). Up-regulation of uPA and uPAR in cancer appears to potentiate the malignant phenotype, either (i) directly by triggering plasmin-mediated degradation or activation of uPA's or plasmin's proteolytic targets (e.g., extracellular matrix zymogen proteases or nascent growth factors) or indirectly by simultaneously altering a range of downstream functions including signal transduction pathways ( Romer, J. ; Nielsen, B. S. ; Ploug, M. The urokinase receptor as a potential target in cancer therapy Curr. Pharm. Des. 2004, 10 ( 19), 235976 ). Because many malignant epithelial cancers express high levels of uPAR, uPA or other components of the plasminogen activation cascade and because these are often associated with poor prognosis, characterizing how uPAR changes the downstream cellular "proteome" is fundamental to understanding any role in cancer. This study describes a carefully designed proteomic study of the effects of antisense uPAR suppression in a previously studied colon cancer cell line (HCT116). The study utilized replicate 2DE gels and two independent gel image analysis software packages to confidently identify 64 proteins whose expression levels changed (by > or =2 fold) coincident with a moderate ( approximately 40%) suppression of cell-surface uPAR. Not surprisingly, many of the altered proteins have previously been implicated in the regulation of tumor progression (e.g., p53 tumor suppressor protein and c-myc oncogene protein among many others). In addition, through a combination of proteomics and immunological methods, this study demonstrates that stathmin 1alpha, a cytoskeletal protein implicated in tumor progression, undergoes a basic isoelectric point shift (p I) following uPAR suppression, suggesting that post-translational modification of stathmin occur secondary to uPAR suppression. Overall, these results shed new light on the molecular mechanisms involved in uPAR signaling and how it may promulgate the malignant phenotype.
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PMID:Differential proteome expression associated with urokinase plasminogen activator receptor (uPAR) suppression in malignant epithelial cancer. 1880 75

Terpyridineplatinum(II) complexes (TPCs) efficiently inhibit the proliferation of glioblastoma cells in vitro and have been tested successfully in a rodent glioblastoma model. Apart from intercalation with DNA, the major mechanism of action of TPCs is a very potent and specific interaction with the human selenoprotein thioredoxin reductase (TrxR). TrxR plays a crucial role in cellular redox homeostasis and protection against oxidative damage. In many malignant cells the thioredoxin system is upregulated, promoting tumor growth and progression. Thus, the thioredoxin system has been proposed to be an attractive target for cancer therapy. This study gives the first comprehensive overview of the effects of TPCs on the transcriptome and proteome of glioblastoma cells. We reveal that under TPC treatment, mechanisms countersteering TrxR inhibition are activated in parallel to DNA-damage-responsive pathways. TPC pressure results in long-term compensatory upregulation of TrxR expression. In parallel, p53 is activated, leading to a range of regulations typical for cell-cycle-arrested cells such as upregulation of CDKN1A, induction of GADD45, inhibition of eIF5A maturation, and reduced phosphorylation of stathmin. We also show that TPCs induce endoplasmic reticulum stress, as they activate the unfolded protein response. This profiling study provides a thorough insight into the spectrum of cellular events resulting from specific TrxR inhibition and characterizes the TPC mode of action.
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PMID:Differential genomic and proteomic profiling of glioblastoma cells exposed to terpyridineplatinum(II) complexes. 1943 28


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