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)

Okadaic acid, a phosphatase inhibitor from a marine organism, mimics tumor necrosis factor/interleukin-1 (TNF/IL-1) in inducing changes in early cellular protein phosphorylation. A total of approximately 116 proteins exhibit significant and concordant changes in phosphorylation or dephosphorylation within 15 min in human fibroblasts activated by either okadaic acid, TNF, or IL-1. The fidelity of this mimicry by okadaic acid extends to the phosphorylation of the 27 hsp complex, stathmin, eIF-4E, myosin light chain, nucleolin, epidermal growth factor receptor, and other cdc2-kinase substrates (c-abl, RB, and p53). The okadaic acid-induced pattern of protein phosphorylation is distinct from that observed in cells treated with phorbol 12-myristate 13-acetate or with ligands like epidermal growth factor, cyclic AMP agonists, bradykinin, or interferons. Like TNF, okadaic acid also induces the transcription of immediate early response genes like c-jun and Egr-1 as well as the interleukin-6 genes. The overall early effects of okadaic acid uniquely parallel those of TNF/IL-1 and not those of other cytokines or ligands. Regulation of protein phosphatase inhibition is discussed as a mechanism for TNF/IL-1 signal transduction.
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PMID:Okadaic acid mimics multiple changes in early protein phosphorylation and gene expression induced by tumor necrosis factor or interleukin-1. 137 Apr 82

Studies of the roles of oncoproteins in cell cycle progression have concentrated on G1 because transformation is frequently associated with loss of G1 checkpoint control. However, it has become evident that G2 and mitotic checkpoints are often compromised in transformed cells and that many tumour suppressor proteins and oncoprotein kinases regulate and/or are activated in G2 and M. Disruption of p53 and ATM tumour suppressor protein functions can eliminate G2 and M checkpoints. The Src family kinases are activated in mitosis and collectively play an indispensable role in progression through G2/M. In addition, evidence suggests that Mos and elements of the Ras/Raf/MAPK cascade are also active in mitosis and appear likely to regulate G2 and/or M. Potential targets of these kinases include likely regulators of gene expression and microtubule dynamics such as Sam68 and Oncoprotein 18/stathmin. The ability of some oncoproteins to perturb orderly progression through both G1 and/or S and G2 and/or M is probably important for transformation.
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PMID:Oncoprotein signalling and mitosis. 921 24

The S100 family of calcium binding proteins has been shown to be involved in a variety of physiological function, such as cell proliferation, extracellular signal transduction, intercellular adhesion, motility as well as cancer metastasis. The role played by a member of the S100 gene family, viz. S100A4 (also referred to as mtsl, 18A2/mtsl, pEL-98, p9Ka, metastasin) in the control of cell proliferation as well as in cancer invasion and metastasis has now been extensively studied in a number of laboratories. The protein encoded by S100A4 gene is now known to be capable of regulating cell cycle progression, modulating intercellular adhesion and invasive and metastatic properties of cancer cells. The S100A4 protein appears to be able to sequester and disable the p53 suppressor protein which controls G1-S transition of cells as well as the exit of cells from the S phase into mitosis G2-M transition is believed to involve the induction of stathmin (Op18) gene expression. The expression of this gene has been found to parallel that of S100A4, S100A4 also appears to take part in the homeostasis of growth, with apparent involvement also in growth factor signal transduction and apoptotic cell death. There is considerable evidence that S100A4 expression alters the adhesive properties of cells, possibly by remodelling the extracellular matrix and promoting a redeployment of adhesion-mediating macromolecules occurring in the extracellular matrix. Using transfection technology, it has been shown that over-expression of S100A4 enhances lung colonisation by cancer cells. The transfection and expression of antisense constructs, in contrast, inhibit metastatic localisation in the lung. S100 proteins levels in serum and in tumour tissue are increasingly being monitored and have been regarded as good indicators of the state of cancer progression. Valuable evidence has accumulated regarding the expression of S100A4 in human melanomas. In carcinoma of the breast, the level of expression of S100A4 has been found to be closely related to metastatic spread of the cancer to regional lymph nodes. The purpose of this review is to emphasise the need to focus sharply upon the mechanisms by which S100 proteins in general and S100A4 in particular subserve the wide variety of functions currently attributable to them.
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PMID:S100A4 (MTS1) calcium binding protein in cancer growth, invasion and metastasis. 970 88

There is growing evidence that the p53 tumor suppressor protein not only can function to activate gene transcription but also to repress the expression of specific genes. Although recent studies have implicated the transcriptional repression function of p53 in the pathway of apoptosis, the molecular basis of this activity remains poorly understood. This study takes a first step toward elucidating this mechanism. We report that trichostatin A (TSA), an inhibitor of histone deacetylases (HDACs), abrogates the ability of p53 to repress the transcription of two genes that it negatively regulates, Map4 and stathmin. Consistent with this finding, we report that p53 physically associates in vivo with HDACs. This interaction is not direct but, rather, is mediated by the corepressor mSin3a. Both wild-type p53 and mSin3a, but not mutant p53, can be found bound to the Map4 promoter at times when this promoter preferentially associates with deacetylated histones in vivo. Significantly, inhibition of p53-mediated transcriptional repression with TSA markedly inhibits apoptosis induction by p53. These data offer the first mechanistic insights for p53-mediated transcriptional repression and underscore the importance of this activity for apoptosis induction by this protein.
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PMID:Transcriptional repression by wild-type p53 utilizes histone deacetylases, mediated by interaction with mSin3a. 1052 94

The p53 tumor suppressor protein can function as an activator and a repressor of gene transcription. Currently, the mechanism of transcriptional repression by p53 is poorly understood. To aid in clarifying this mechanism, we carried out studies designed to identify specific target genes that are down-regulated following p53 induction. Among the negative p53-response genes revealed by our screening protocols are those encoding stathmin (Op18), a tubulin-associated protein implicated in cell signaling pathways, and an FK506/rapamycin-binding protein, FKBP25. Stathmin and FKBP25 exhibit decreased expression in both human and murine immortalized and transformed cell lines following induction of wild-type p53 by several stimuli that result in DNA damage. Candidate p53-repressed genes such as these provide the necessary markers to delineate the mechanism and biological consequences of transcriptional repression mediated by p53.
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PMID:Down-regulation of the stathmin/Op18 and FKBP25 genes following p53 induction. 1055 83

Utilizing the technique of differential display of mRNA, we have identified p53-responsive genes that are transcriptionally up- or down-regulated as cells enter growth arrest. One gene that was down-regulated, pong16, was found to be identical to stathmin/Op18, a protein involved in the regulation of microtubule dynamics. Evidence that p53 is directly or indirectly involved in negative regulation of stathmin/Op18 expression includes the following: (i) p53-mediated growth inhibition is associated with repression of stathmin/Op18 expression following serum stimulation, (ii) reporter gene assays revealed p53-mediated repression of stathmin/Op18 promoter activity and (iii) constitutive over-expression of stathmin/Op18 bypasses a p53-mediated G(2)/M arrest in the cell cycle. These results suggest that p53-mediated negative regulation of stathmin/Op18 plays an important role in cell-cycle control.
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PMID:p53-mediated negative regulation of stathmin/Op18 expression is associated with G(2)/M cell-cycle arrest. 1107 34

S100A4 is a cell proliferation- and cancer metastasis-related gene. Previous studies have shown that over-expression of S100A4 drives the cells into the S-phase of the cell cycle, with concomitant enhancement of p53 detection. This has led to the postulate that S100A4 could be controlling cell cycle progression by sequestering p53 and abrogating its G1-S checkpoint control. Cells induced by S100A4 to enter the S-phase do successfully negotiate the G2-M checkpoint control. Here we show that S100A4 is also involved in the regulation of control at this checkpoint. Stathmin is known to be associated, together with p53 in controlling G2-M transition. We present evidence that the expression of S100A4 and stathmin genes is up regulated in exponentially growing HeLa cells. They are down regulated in parallel when cell proliferation is inhibited by hyperthermia and 4-hydroxynonenal (4-HNE). We postulate that S100A4 might directly induce stathmin up regulation to enable cells to enter into mitosis. Since wild-type p53 is known to down regulate stathmin expression, we further postulate this might also involve S100A4-mediated sequestration of p53. The expression of heme oxygenase (HO-1), a stress-response protein, has been used to monitor effects of hyperthermia, 12-O-tetradecanoly phorbol 13-acetate (TPA) and 4-HNE. All these treatments induced HO-1 and also when cells growing in serum-deficiency were restored with full serum. HO-1 induction occurred irrespective of S100A4 expression status. HO-1 gene has responsive elements for many angiogenic agents and induces marked neovascularisation of tumours. We suggest therefore that S100A4 may not possess angiogenic properties.
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PMID:Stathmin is involved in S100A4-mediated regulation of cell cycle progression. 1108 85

Stathmin is a p53-regulated protein known to influence microtubule dynamics. Because several chemotherapeutic agents used to treat breast cancer alter the dynamic equilibrium of tubulin polymerization, stathmin may play an important role in determining the sensitivity to these drugs. Therefore, we evaluated the effect of stathmin expression on the action of taxanes and Vinca alkaloids using a panel of human breast cancer cell lines. Cell lines harboring mutant p53 expressed high levels of stathmin. Two cell lines with different levels of endogenous stathmin expression and isogenic-paired cell lines transfected to overexpress stathmin were used to determine whether or not stathmin modulated the sensitivity to drugs. Overexpression of stathmin decreased polymerization of microtubules, markedly decreased binding of paclitaxel, and increased binding of vinblastine. Stathmin overexpression decreased sensitivity to paclitaxel and, to a lesser extent, to vinblastine. In contrast, stathmin content had no significant effect on the sensitivity to chemotherapeutic drugs that do not target microtubules. Cell lines overexpressing stathmin were more likely to enter G(2) but less likely to enter mitosis as determined by fluorescence-activated cell sorting and mitotic index. This effect was magnified when stathmin-overexpressing cells were treated with vinblastine as measured by the detection of proteins phosphorylated in early mitosis. These data suggest that the action of antimicrotubule drugs can be affected by stathmin in at least two ways: (a) altered drug binding; and (b) growth arrest at the G(2) to M boundary. Mutant p53 breast cancers exhibiting high levels of stathmin may be resistant to antimicrotubule agents.
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PMID:Effect of stathmin on the sensitivity to antimicrotubule drugs in human breast cancer. 1246 Sep

The tumor suppressor p53 regulates transcription positively and negatively, depending on the target gene. Whereas p53 induces transcription through direct interaction with promoter DNA, the mechanism of p53-mediated transcriptional repression is less well understood. Early reports described the alleviation of p53-mediated repression by inhibitors of apoptosis, suggesting that negative regulation of transcription might occur only in conjunction with programmed cell death. More recently, it has been proposed that certain genes, such as survivin, are repressed by direct association of p53 with their promoters, followed by recruitment of a repressor complex. We show here that p53-mediated negative regulation of transcription could occur independently of apoptosis. In contrast, the amino-terminal transactivation domain of p53 was required for negative regulation of transcription. Similarly, the p53 homologue p73 diminished the expression of survivin and stathmin, depending on its transactivation domain. Mutation of the putative p53 binding site within the survivin promoter did not impair its repression. These observations raised the hypothesis that activation of an effector gene might be required for repression by p53. Strikingly, when the p53-inducible p21/CDKN1A gene was deleted, p53 no longer repressed any one among 11 genes that it down-regulates otherwise. Most of these genes were also repressed by ectopic p21 in the absence of p53. Overexpressed c-Myc reduced the transcription of p21/CDKN1A and impaired p53-mediated repression but did not abolish repression by ectopic p21. Taken together, these results strongly suggest that increased expression of p21/CDKN1A is necessary and sufficient for the negative regulation of gene expression by p53.
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PMID:p21/CDKN1A mediates negative regulation of transcription by p53. 1274 90

Two paclitaxel(Ptx)-resistant ovarian cancer cell lines, 1A9/Ptx-10 and 1A9/Ptx-22, isolated from the 1A9 cell line (a clone of the A2780 line) by continuous exposure to Ptx and verapamil, have point mutations in their major beta-tubulin gene and in one or both alleles of their TP53 gene. These cells were examined for alterations in cell cycle regulators and the tubulin-binding protein stathmin. Unlike parental cells, neither 1A9/Ptx-10 nor 1A9/Ptx-22 expressed detectable levels of p21(WAF1/Cip1), a putative transcriptional regulator of stathmin, but did overexpress stathmin and Bcl2. No differences were noted in the expression levels of proliferative cell nuclear antigen or tyrosine-phosphorylated p34Cdc2. Ptx treatment altered little the expression of stathmin in the parental cell line, although it increased p21(WAF1/Cip1) levels several-fold. Infection of Ptx-resistant lines with a wild-type TP53-bearing adenovirus (AdWTp53) changed cell cycle distribution and increased the levels of p21(WAF1/Cip1), but caused no changes in stathmin levels. Microtubule drug resistance in ovarian carcinoma may be associated with altered p53/21(WAF1/Cip1) regulatory pathways for stathmin expression and function.
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PMID:Altered levels and regulation of stathmin in paclitaxel-resistant ovarian cancer cells. 1465 88


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