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)

Testicular germ cell cancers remain one of the few solid tumors routinely cured in advanced stages with conventional cisplatin-based chemotherapy. The mechanisms remain largely unknown. Through use of gene-expression array profiling we define immediate transcriptional targets in response to cisplatin in testicular germ cell-derived human embryonal carcinoma cells. We report 46 genes upregulated and five genes repressed by cisplatin. Several of these gene products, including FAS, TRAILR3, PHLDA3, LRDD, and IER3 are previously implicated in the apoptotic death receptor pathway, while others including SESN1, FDXR, PLK3, and DDIT4 are known mediators of reactive oxygen species generation. Approximately 54% of the upregulated genes are established or suspected downstream targets of p53. Specific siRNA to p53 prevents cisplatin-mediated activation of p53 and p53 pathway genes and renders embryonal carcinoma cells relatively resistant to cisplatin cytotoxicity. Interestingly, in p53 knockdown cells nearly the entire set of identified cisplatin targets fail to respond or have a diminished response to cisplatin, suggesting that many are new direct or indirect targets of p53 including GPR87, STK17A, INPP5D, FLJ11259, and EPS8L2. The data indicate that robust transcriptional activation of p53 is linked to the known hypersensitivity of testicular germ cell tumors to chemotherapy. Many of the gene products may participate in the unique curability of this disease.
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PMID:A p53-dominant transcriptional response to cisplatin in testicular germ cell tumor-derived human embryonal carcinoma. 1594 Feb 59

Although the majority of testicular germ cell tumors (TGCTs) are curable by cisplatin-based chemotherapy, in a few cases, the occurrence of cisplatin resistance results in a poor outcome. The biological basis of this differential cisplatin sensitivity in TGCTs remains largely unexplained. Embryonal carcinoma (EC) cells represent the presumptive tumor stem cells in nonseminomatous TGCTs and are known to express the embryonal transcription factor Oct-3/4 and to be hypersensitive to cisplatin. In the present study, we analyzed TGCT cell lines and nude mouse xenografts showing differential cisplatin sensitivity. Here we demonstrate that a lack of expression of Oct-3/4 in TGCT cells is associated with a higher apoptotic threshold and cisplatin resistance which is accompanied by an impaired caspase-9 activation, reduced caspase-3 activity and altered p53 accumulation. We were able to induce loss of Oct-3/4 in a cisplatin-sensitive EC cell line resulting in a secondary cisplatin-resistant cell type with retained EC cell characteristics and changes in apoptotic signaling identical to those in primary resistant cells. Furthermore, we show that EC cells are retained in their undifferentiated state by Oct-3/4 and that a complete and ultimate loss of Oct-3/4 followed by an early differentiation step is necessary to establish the cisplatin-resistant state. Our data suggest that loss of Oct-3/4 expression leads to induction of a higher apoptotic threshold and to cisplatin resistance in EC cells of nonseminomatous TGCTs. We hypothesize that in refractory TGCTs the original tumor stem cell population of Oct-3/4-positive, cisplatin-sensitive EC cells could be replaced by an Oct-3/4-negative, resistant population in a selection process. In contrast, the presence of the Oct-3/4-positive, highly sensitive EC cells as the tumor stem cell component in most TGCTs could explain the general high chemosensitivity and curability of these tumors.
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PMID:Loss of Oct-3/4 expression in embryonal carcinoma cells is associated with induction of cisplatin resistance. 1655 44

Primary intracranial germ cell tumors (GCTs) comprise 3.1% of all brain tumors and 13.6% of those in patients younger than 15 years of age in Japan. They are classified into five basic histological types: germinoma, teratoma, choriocarcinoma, yolk sac tumor, and embryonal carcinoma; or into mixed tumor types when they consist of two or more components. Radiation therapy with or without chemotherapy has proven effective in the treatment of germinoma, whereas there is a poor prognosis for choriocarcinoma, yolk sac tumor, embryonal carcinoma, and mixed tumors having components of the group of malignant intracranial GCTs. The underlying mechanisms for such different responses to radio- and chemotherapies of intracranial GCTs remain unknown. In this study, the authors analyzed the expression of p53 and p21(WAF1/Cip1) proteins by immunohistochemical analysis in 35 intracranial GCTs. Expression of p53 protein was observed in 33 (94%) of 35 intracranial GCTs. Expression of p21(WAF1/Cip1) was detected in seven (20%) of 35 intracranial GCTs. None of the 15 germinomas was immunoreactive for p21(WAF1/Cip1) protein, whereas in a group of malignant intracranial GCTs, four (80%) of five cases showed immunoreactivity for p21(WAF1/Cip1) protein. Analysis of the data suggests that overexpression of p21(WAF1/Cip1) in intracranial GCTs may correlate with decreased sensitivity to radio- and chemotherapy and suggest a poor prognosis.
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PMID:Immunohistochemical analysis of p53 and p21(WAF1/Cip1) expression in primary intracranial germ cell tumors. 1714 Jan 83

Li-Fraumeni syndrome is an autosomal dominant disorder that greatly increases the risk of developing multiple types of cancer. The majority of Li-Fraumeni syndrome families contain germ-line mutations in the p53 tumor suppressor gene. We describe treatment of a refractory, progressive Li-Fraumeni syndrome embryonal carcinoma with a p53 therapy (Advexin) targeted to the underlying molecular defect of this syndrome. p53 treatment resulted in complete and durable remission of the injected lesion by fluorodeoxyglucose-positron emission tomography scans with improvement of tumor-related symptoms. With respect to molecular markers, the patient's tumor had abnormal p53 and expressed coxsackie adenovirus receptors with a low HDM2 and bcl-2 profile conducive for adenoviral p53 activity. p53 treatment resulted in the induction of cell cycle arrest and apoptosis documented by p21 and cleaved caspase-3 detection. Increased adenoviral antibody titers after repeated therapy did not inhibit adenoviral p53 activity or result in pathologic sequelae. Relationships between these clinical, radiographic, and molecular markers may prove useful in guiding future application of p53 tumor suppressor therapy.
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PMID:p53 therapy in a patient with Li-Fraumeni syndrome. 1748 35

Human germ-cell tumors (GCTs) are a heterogeneous group of neoplasms. Based on epidemiology, anatomical site of presentation, histology, chromosomal constitution, and pattern of genomic imprinting, GCTs are classified into five entities. Within the testis, three types of GCTs can be diagnosed: type I (teratomas and yolk-sac tumors of neonates and infants); type II (seminomas and nonseminomas); type III (spermatocytic seminomas). Here the focus is on the type II GCTs, the most frequent type in the adult testis (so-called TGCTs). They can also be diagnosed in dysgenetic gonads (an incomplete or defective formation of the gonad, caused by a disturbed process of migration of the germ cells and/or their correct organization in their fetal gonadal ridge), the anterior mediastinum, and pineal/suprasellar region. In the testis, they originate from the malignant counterpart of primordial germ cells/gonocytes, referred to as carcinoma in situ (CIS)/intratubular germ-cell neoplasia unclassified (ITGCNU). CIS/ITGCNU and seminomatous cells are characterized by expression of OCT3/4 and NANOG, while in addition embryonal carcinoma expresses SOX2, all identified as transcription factors related to pluripotency in embryonic stem (ES) cells. With the exception of teratomas, most histological elements of TGCTs are sensitive for (cisplatin-based) chemotherapy; CIS/ITGCNU and seminoma cells are also sensitive to DNA damage induced by irradiation. Similar observations have been made for ES cells and their derivates. Moreover, the genetic constitution of TGCTs (low incidence of mutations and frequent uniparental disomies) can also be linked to characteristics of ES cells, likely related to their specific inability to repair DNA damage and their high sensitivity to apoptotic cell death. The unusual presence of wild-type P53 in TGCTs is explained by specific expression of a cluster of micro-RNAs (miRNAs), that is, hsa-miR 371-373, also expressed in ES cells, which prevents P53-driven cellular senescence upon oncogenic stress. Many characteristics of human TGCTs reflect the nonmalignant counterparts from which they originate. Demonstration of these characteristics, in combination with the knowledge of the abnormal niche of these cells, normally occupied by spermatogonia, allows an informative method for (early) diagnosis. The conclusion is that TGCTs are embryonic cancers found in adults.
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PMID:Chromosomes and expression in human testicular germ-cell tumors: insight into their cell of origin and pathogenesis. 1791 10

Necdin (NDN), a member of the melanoma-associated antigen (MAGE) family of proteins was first identified in mouse stem cells of embryonal carcinoma origin induced to differentiate by treatment with retinoic acid. The human gene maps to chromosome 15q11. This imprinted region is implicated in the pathogenesis of Prader-Willi syndrome (PWS), a neurodevelopmental disorder, where NDN is one of multiple genes silenced by deletion, maternal uniparental disomy or translocation. Due to this association, much interest has focused on the role of NDN in neuronal development and differentiation. However, a considerable number of studies have identified additional functions of NDN. Taken together these studies suggest a pleiotropic protein with diverse functions some of which may be relevant to tumorigenesis. Downregulation of NDN occurs in carcinoma cell lines and primary tumors, suggesting a tumor suppressor role. Our working hypothesis is that NDN is a worthy candidate for further studies with regard to a potential tumor suppressor role. In this article we outline the considerable evidence supporting the hypothesis that NDN has multiple functions, some of which indicate that it could be a tumor suppressor. The roles of NDN in key processes such as interaction with p53 and E2F-1, hematopoietic stem cell quiescence, transcriptional repression, angiogenesis, differentiation and interaction with the polycomb group gene BMI1 are discussed. Confirmation of NDN as a tumor suppressor may have implications for monitoring of PWS patients and could present a novel cancer therapeutic target.
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PMID:Necdin: a multi functional protein with potential tumor suppressor role? 1962 46

Cancer stem cells are expected to be responsible for tumor initiation and metastasis. These cells are therefore potential targets for innovative anticancer therapies. However, the absence of bona fide cancer stem cell lines is a real problem for the development of such approaches. Since teratocarcinoma cells are totipotent stem cells with a high degree of malignancy, we used them as a model of cancer stem cells in order to evaluate the anticancer chemopreventive activity of red wine polyphenols (RWPs) and to determine the underlying cellular and molecular mechanisms. We therefore investigated the effects of RWPs on the embryonal carcinoma (EC) cell line P19 which was grown in the same culture conditions as the most appropriate normal cell line counterpart, the pluripotent embryonic fibroblast cell line NIH/3T3. The present study indicates that RWPs selectively inhibited the proliferation of P19 EC cells and induced G1 cell cycle arrest in a dose-dependent manner. Moreover, RWPs treatment specifically triggered apoptosis of P19 EC cells in association with a dramatic upregulation of the tumor suppressor gene p53 and caspase-3 activation. Our findings suggest that the chemopreventive activity of RWPs on tumor initiation and development is related to a growth inhibition and a p53-dependent induction of apoptosis in teratocarcinoma cells. In addition, this study also shows that the EC cell line is a convenient source for studying the responses of cancer stem cells to new potential anticancer agents.
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PMID:Selective proapoptotic activity of polyphenols from red wine on teratocarcinoma cell, a model of cancer stem-like cell. 1994 82

Apoptotic protease activating factor-1 (APAF-1) is a key regulator gene of apoptosis, located downstream from p53. Loss of APAF-1 expression is associated with chemorefractory malignant melanoma and neuronal cell differentiation. In order to make clear the function of APAF-1 in the carcinogenesis of germ cell tumors, we evaluated the expression levels of APAF-1 and several apoptosis and differentiation markers by immunohistochemistry in formalin-fixed paraffin-embedded samples from 43 cases of testicular germ cell tumor (TGCT) and six specimens of normal testis tissue. Expression of cleaved caspase-3, Oct-3/4, and Ki-67 were also examined by immunohistochemistry to evaluate apoptotic reactivity, tumor differentiation, and proliferation activity, respectively. APAF-1 was downregulated in two TGCT cell lines by siRNA transfection, and subsequent expression of the Ki-67 and Oct-3/4 genes and differentiation markers of three embryonic germ layers including keratin16 (KRT16) for ectoderm, vimentin (VIM) for mesoderm and GATA4 for endoderm were then tested. No significant relationship was found between APAF-1 expression and apoptotic activity in TGCTs. Expression of APAF-1, Oct-3/4, and Ki-67 was significantly higher in seminomas than in non-seminomas. In TGCTs, higher APAF-1 expression was correlated with higher proliferation (high Ki-67) and a lower degree of differentiation (high Oct-3/4). Interestingly, the expression of APAF-1 gradually decreased in accordance with tumor differentiation (seminoma and embryonal carcinoma > teratoma). Downregulation of APAF-1 in TGCT cell lines resulted in a decrease of Ki-67 and Oct-3/4 and an increase of VIM and KRT16 gene expression. These data show that higher expression of APAF-1 is related to an undifferentiated state in the TGCT pathway.
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PMID:APAF-1 is related to an undifferentiated state in the testicular germ cell tumor pathway. 2097 44

Earlier studies identified testes-specific protease 50 (TSP50), which encodes a threonine protease, and showed that it was abnormally reactivated in many breast cancer biopsies. Further, it was shown to be negatively regulated by the p53 gene. However, little is known about the biological function of TSP50. In this study, we applied RNA interference to knockdown TSP50 gene expression in P19 murine embryonal carcinoma stem cells and tested whether this modulated the cell phenotype. The results showed that downregulation of TSP50 expression not only reduced cell proliferation, colony formation, and migration but also induced cell apoptosis. Further investigation revealed that knockdown of TSP50 resulted in greater sensitivity to doxorubicin-induced apoptosis and that activation of caspase-3 was involved in this process.
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PMID:Knockdown of TSP50 inhibits cell proliferation and induces apoptosis in P19 cells. 2108 74

Use of chemotherapeutic drug cisplatin is limited because of its toxicity. Therefore, efforts continue for the discovery of novel combination therapies with cisplatin to reduce its effective treatment dose. This study evaluates the potential of fisetin, a flavonoid, to increase cisplatin cytotoxicity in human embryonal carcinoma NT2/D1 cells. Addition of fisetin to cisplatin enhanced cisplatin cytotoxicity in vitro at four times lower dose than that required by cisplatin monotherapy for similar cytotoxic effects. Cisplatin, fisetin monotherapy, and addition of fisetin to cisplatin in a combination increased FasL expression. Cisplatin and fisetin as single agents activated caspases-8 and -3 and caspases-9 and -7, respectively, whereas combination treatment activated all 4 caspases. Increases in p53 and p21 and decreases in cyclin B1 and survivin occurred, all effects being more exaggerated with the combination. Fisetin, with or without cisplatin, increased expression of proapoptotic protein Bak and induced its mitochondrial oligomerization. Bid truncation and mitochondrial translocation of Bid and p53 was induced by fisetin in the presence or absence of cisplatin. Downregulation of p53 by short hairpin RNA during drug treatment decreased p21 levels but caused survivin increase, thus reducing cell death. Upstream to p53, inhibition of p38 phosphorylation reduced p53 phosphorylation and cell death. In a NT2/D1 mouse xenograft model, combination therapy was most effective in reducing tumor size. In summary, findings of this study suggest that addition of fisetin to cisplatin activates both the mitochondrial and the cell death receptor pathway and could be a promising regimen for the elimination of embryonal carcinoma cells.
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PMID:Anticancer activity of a combination of cisplatin and fisetin in embryonal carcinoma cells and xenograft tumors. 2121 35


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