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)

In this study, we examined the cellular and molecular responses of fibroblasts cultured on a polyelectrolyte complex (PEC) derived from sulfated chitin as a polyanion and chitosan as a polycation. On PEC-coated dishes, the fibroblasts aggregated and then developed spheroid-like structures. At earlier stages of culture, DNA synthesis of cells cultured on PEC was stimulated approximately 75% higher than control cells. Among various signaling molecules examined, including mitogen-activated protein kinases, Akt/PKB and p53, an extracellular-signal-regulated kinase (ERK) was selectively and constitutively phosphorylated in cells cultured on PEC. The constitutive phosphorylation of ERK was derived from an activation of the ERK kinase MEK, but not from an inactivation of the ERK phosphatase MKP-1. Furthermore, ERK phosphorylation was almost abolished by a membrane receptor tyrosine kinase inhibitor. The enhanced phosphorylation of focal adhesion kinase, a downstream molecule of integrins, was also observed in cells cultured on PEC. These results suggest that fibroblasts recognize PEC as a continuous mitogenic stimulant which results in the constitutive activation of the MEK-ERK pathway toward mitogenesis. Further, PEC interacts with the cell membrane leading to activation of membrane molecules, including integrins and receptor tyrosine kinases. These responses may account, at least in part, for the potential use of PEC as a biomaterial for tissue regeneration.
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PMID:Enhanced DNA synthesis accompanied by constitutive phosphorylation of the ERK pathway in human fibroblasts cultured on a polyelectrolyte complex. 1453 74

Glucocorticoids (GC) such as hydrocortisone and dexamethasone (DEX) protect steroidogenic granulosa cells against apoptosis induced by serum deprivation, cAMP, tumor necrosis factor alpha stimulation or p53 activation. The protective effects were evident both in primary rat and human granulosa cells, which comprise the main population of the ovarian follicular cells, as well as in steroidogenic granulosa cell lines established in our laboratory. A correlation between the expression of Bcl-2 protein and protection against apoptosis induced by DEX was found in granulosa cell lines expressing various levels of Bcl-2. Incubation with DEX leads to development of a rigid network of actin cytoskeleton and increased incidence of adherence and gap junctions. Higher content of connexin 43 and total cadherins were found in GC stimulated cells compared to non-stimulated, suggesting that cell contact and intracellular communication contribute to the DEX induced resistance to apoptotic signals. Activation by DEX of MAPK and Akt/PKB but not p38 supported the view of a pleiotropic action of GC against apoptotic signals. Granzyme B, a protease characteristic for induction of apoptosis by T-cytotoxic lymphocytes and natural killer cells, was expressed and augmented during stimulation of apoptosis in the granulosa cells, and its synthesis and activation was blocked by DEX. It is concluded that GC exerted their anti-apoptotic effects in granulosa cells by multiple characteristic pathways. Moreover, the presence of endogenous granzyme B in granulosa cells suggest a novel intrinsic alternative apoptotic pathway that was earlier reported to be mediated uniquely by T-cytotoxic lymphocytes and natural killer cells. The anti-apoptotic effect of GC may play an important role in the healing process of the ovulatory follicle subsequent to follicular rupture and its rapid conversion to an active corpus luteum.
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PMID:Pleiotropic anti-apoptotic activity of glucocorticoids in ovarian follicular cells. 1455 13

Cisplatin is one of the most potent antitumor agents known, displaying clinical activity against a wide variety of solid tumors. Its cytotoxic mode of action is mediated by its interaction with DNA to form DNA adducts, primarily intrastrand crosslink adducts, which activate several signal transduction pathways, including those involving ATR, p53, p73, and MAPK, and culminate in the activation of apoptosis. DNA damage-mediated apoptotic signals, however, can be attenuated, and the resistance that ensues is a major limitation of cisplatin-based chemotherapy. The mechanisms responsible for cisplatin resistance are several, and contribute to the multifactorial nature of the problem. Resistance mechanisms that limit the extent of DNA damage include reduced drug uptake, increased drug inactivation, and increased DNA adduct repair. Origins of these pharmacologic-based mechanisms, however, are at the molecular level. Mechanisms that inhibit propagation of the DNA damage signal to the apoptotic machinery include loss of damage recognition, overexpression of HER-2/neu, activation of the PI3-K/Akt (also known as PI3-K/PKB) pathway, loss of p53 function, overexpression of antiapoptotic bcl-2, and interference in caspase activation. The molecular signature defining the resistant phenotype varies between tumors, and the number of resistance mechanisms activated in response to selection pressures dictates the overall extent of cisplatin resistance.
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PMID:Cisplatin: mode of cytotoxic action and molecular basis of resistance. 1457 37

Although it is known that high levels of cigarette smoke lead to cell death, little is known about the effects of low-to-moderate levels of smoke components that are found in vivo, such as those experienced by cells in tissues. Clinical studies and experimental data show that smokers heal poorly and are more prone to develop fibrotic diseases. Here we show the effects of first-hand cigarette smoke on fibroblasts, cells that are critically involved in these processes. Using doses of smoke found in the tissues of smokers and a variety of cell and molecular approaches, we show that these doses of cigarette smoke do not cause cell death but rather stimulate fibroblasts to produce stress response and survival proteins such as interleukin-8, PKB/Akt, p53, and p21 that in turn contribute to an increase in cell survival. In addition, smoke-treated cells show a decrease in cell migration, which can be explained by the increased cell adhesion and alterations in cytoskeletal elements. We also show that these levels of smoke cause changes in mitochondrial morphology with a minimum loss of function and these changes are the result of exposure to reactive oxygen species. We conclude that the increase in cell survival may lead to a build-up of connective tissue in the area of a wound, potentially leading to delayed healing and/or fibrosis and that the alterations in the cytoskeleton and in cell adhesion result in inhibition of cell migration, a process that could lead to nonclosure of the wound for lack of proper fibroblast migration to form the healing tissue.
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PMID:Firsthand cigarette smoke alters fibroblast migration and survival: implications for impaired healing. 1526 Aug 13

A multicenter phase II trial was conducted to define the activity of letrozole in postmenopausal women with recurrent or advanced endometrial carcinoma, who had no more than one prior line of progestins and never had chemotherapy (except adjuvant). Archival paraffin-embedded tumor samples were retrieved to determine the expression level of estrogen (ER) and progesterone receptor (PgR), p53, HER-2, bcl-2 and PTEN protein, and phosphorylation status of protein kinase B (PKB/Akt). Thirty-two eligible patients were treated with letrozole at 2.5 mg daily continuously, of whom 10 (31%) had prior progestins. Of the 28 patients evaluated for response, one complete and two partial responses were noted; overall response was 9.4% (95% confidence interval 2-25%). Eleven patients had stable disease for a median duration of 6.7 months (range 3.7-19.3 months). Amongst 22 patients who had tumor blocks available, the proportion showing positive expression of the following markers includes: PgR (86%), ER (86%), PTEN (82%), phosphorylated PKB/Akt (59%), bcl-2 (45%), p53 (32%), and HER-2 (0%). None of these markers correlated with response to letrozole or disease progression. In conclusion, letrozole is well tolerated but has little overall activity in this cohort of women with endometrial cancer.
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PMID:The activity of letrozole in patients with advanced or recurrent endometrial cancer and correlation with biological markers--a study of the National Cancer Institute of Canada Clinical Trials Group. 1530 61

Decidualization of the endometrial stromal compartment is critical for embryo implantation. Initiation of this differentiation process requires elevated intracellular cAMP levels. We now report a massive and sustained up-regulation of p53 tumor suppressor protein during cAMP-induced decidualization of cultured endometrial stromal cells. Nuclear accumulation of p53 was not accompanied by increased mRNA expression, suggesting stabilization of the protein as the underlying mechanism. Proteasomal degradation of p53 is known to be mediated by nuclear Mdm2. Nuclear translocation of Mdm2, in turn, is dependent on phosphorylation by protein kinase B/Akt (PKB/Akt). In cAMP-treated decidualized cells, p53 accumulation was associated with decreased nuclear Mdm2 and cytoplasmic PKB/Akt levels. Conversely, withdrawal of the decidualization stimulus resulted in morphological and biochemical dedifferentiation, disappearance of p53, but increased abundance of PKB/Akt. Furthermore, Western blot and immunohistochemical analyses of endometrial biopsies confirmed that p53 is expressed in vivo in the stromal compartment during the late secretory phase of the cycle. The observation that p53 protein expression is closely associated with decidual transformation indicates a novel role for this tumor suppressor in regulating human endometrial function.
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PMID:Wild-type p53 protein is up-regulated upon cyclic adenosine monophosphate-induced differentiation of human endometrial stromal cells. 1547 30

We studied in vitro effects of glycogen synthase kinase 3beta (GSK3beta)-inhibitor lithium on the growth of hepatocellular carcinoma (HCC) cells. Lithium induced strong growth inhibition (> 70%) in 75% (n = 9 of 12) of cell lines, apparently independent from the status of major genes that are mutated in HCC including p53, p16(INK4a), beta-catenin and Axin1. Comparative studies with a growth-sensitive Huh7 and growth-resistant Hep40 cell lines showed that lithium induces growth arrest in Huh7 cells but not in Hep40 cells. Lithium induced the accumulation of N-terminally phosphorylated inactive form of GSK3beta with concomitant increase in beta-catenin and beta-catenin/TCF transcriptional activity in both cell lines. This suggests that lithium-mediated HCC growth inhibition is independent of its well-known stimulatory effect on Wnt-beta-catenin signaling. The main differences between Huh7 and Hep40 responses to lithium treatment were observed at the levels PKB/Akt and cyclin E proteins. Lithium induced depletion of both proteins in growth-sensitive Huh7, but not in growth-resistant Hep40 cells. PKB/Akt and Cyclin E are 2 major proteins that are known to be constitutively active in HCC. The targeting of both proteins with lithium may be the main reason why most HCC cells are responsive to lithium-mediated growth inhibition, independent of their p53, retinoblastoma and Wnt-beta-catenin pathways. The exploration of molecular mechanisms involved in lithium-mediated growth inhibition in relation with PKB/Akt and cyclin E downregulation may provide new insights for therapy of liver tumors.
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PMID:Lithium-mediated downregulation of PKB/Akt and cyclin E with growth inhibition in hepatocellular carcinoma cells. 1572 55

A time course study was performed to reveal the sequence of histopathology after Trichinella spiralis or T. pseudospiralis infection in mice. A cyst was formed in the former case by about 18 days post infection and prominent myopathy was restricted within the cyst. In the latter case, however, no typical cyst was formed, and myopathy spread diffusely over the infected muscle tissues occupying half the area of muscle sections. An electron microscope observation revealed that the disintegration of muscle cells was delayed in T. pseudospiralis infection than in T. spiralis infection. Quantitative reverse transcription polymerase chain reaction (RT-PCR) showed that apoptosis-related genes were expressed for a longer term in muscles infected with T. pseudospiralis than in those with T. spiralis, although the same spectrum of genes are mobilized. Examined apoptosis-related genes included tumor suppressor genes p53, p53; mouse double minute 2, MDM2; cyclin-dependent kinase inhibitor p21 (WAF1), p21(waf) ; Bcl-2 associated protein X, BAX; apoptotic protease activating factor 1, Apaf-1; Caspase 9 and serine/ threonine protein kinase, PKB. Micro-dissection of the infected muscle tissue and subsequent RT-PCR confirmed that the expressions of these genes are restricted to tissue with myopathy. Thus, the expression of the apoptosis-related genes correlated with continuous and diffuse myopathy caused by T. pseudospiralis infection.
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PMID:Trichinella pseudospiralis infection is characterized by more continuous and diffuse myopathy than T. spiralis infection. 1594 11

TRB3 has recently been identified as a potential pro-apoptotic protein that may modulate the Akt/PKB-dependent signaling pathway. Here we report that TRB3 expression is strongly upregulated by endoplasmic reticulum (ER) stress-inducing agents that (1) promote ER Ca2+ pool depletion or (2) disrupt protein trafficking. Genotoxic stress (DNA damage)-inducing agents, by contrast, downregulate TRB3 expression and appear to do so through both p53-dependent and -independent mechanisms. To the best of our knowledge, TRB3 is the first gene that is upregulated by ER stress and downregulated following genotoxic stress. Collectively, these findings highlight the importance of stress-specific signaling cascades as well as point out the seemingly divergent roles that TRB3 may play in the cellular stress response.
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PMID:Genotoxic and endoplasmic reticulum stresses differentially regulate TRB3 expression. 1629 33

After N-acetylglucosaminyltransferase V (GnT-V) activity was down-regulated by the transfection of its antisense cDNA(GnTV-AS), apoptosis of H7721 cells was appeared and the apoptosis induced by 80 microM all-transretinoic acid (ATRA) was facilitated, while ATRA itself could not induce apparent apoptosis in mock cells transfected with the vector. In the study of the molecular mechanism of this phenomenon, it was found that GnTV-AS reduced the expressions of anti-apoptotic proteins, such as phosphorylated protein kinase B and phosphorylated Bad as well as Bcl-2 and Bcl-X (L), and elevated those of pro-apoptotic proteins, including Bax, full length caspase-3 and its activated fragments as well as anti-oncoprotein p53. In the contrast, ATRA up regulated the expressions of Bax and activated caspase-3 fragments only. After the GnTV-AS transfected cells were treated with ATRA, phosphorylated PKB and Bad were further decreased, while Bax and activated caspase-3 fragment were further increased, leading to the enhanced apoptosis in flow-cytometry analysis when compared with GnTV-AS cells not treated with ATRA. It was speculated that the decreased phospho-Bad resulted from the reduced phospho-PKB and the up regulation of p53 caused the elevated activity of Bax. The increased active caspase-3 was the consequence of the elevated Bax/ Bcl-2(Bcl-X(L)) activity ratio in the cells.
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PMID:Down regulation of N-acetylglucosaminyltransferase V facilitates all-transretinoic acid to induce apoptosis of human hepatocarcinoma cells. 1641 Oct 21


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