Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0596263 (carcinogenesis)
64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently PTEN/MMAC1, a candidate tumor suppressor gene, was isolated from chromosome 10q23-24 and somatic mutations of this gene were detected in several malignancies including brain, prostate, and breast tumors. To investigate further the potential role of this gene in mammary carcinogenesis, we examined 69 primary breast cancers for mutations in PTEN/MMAC1 by means of polymerase chain reaction single-strand conformation polymorphism and sequencing analysis. We detected only one somatic missense mutation, a change from T to C at codon 59 (TCA to CCA) resulting in substitution of Pro for Ser in the predicted protein. This site is located outside of phosphatase or phosphate-acceptor motifs, but this codon encodes a residue that is conserved in homologous proteins, tensin and auxilin and is likely to be crucial for normal function of PTEN/MMAC1. Among the 69 tumors examined, three low-frequency polymorphisms were found as well, one in the non-coding region of exon 1 and one each in introns 2 and 7. Our results suggested that mutation of the PTEN/MMAC1 gene is not a major factor in the development of most primary breast cancers.
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PMID:Infrequent mutations in the PTEN/MMAC1 gene among primary breast cancers. 951 Apr 70

Prostate Stem Cell Antigen (PSCA) is a glycosylphosphatidylinositol-anchored cell surface protein that is expressed in normal human prostate and overexpressed in human prostate cancers. To test whether different pathways that generate prostate cancer would affect PSCA expression, a murine model system was developed. Monoclonal antibodies were generated against murine PSCA (mPSCA). mPSCA is expressed on approximately 20% of cells in normal prostate epithelium, and this number decreases with increasing age. In the transgenic adenocarcinoma of the mouse prostate (TRAMP) model of prostate cancer, tumors develop between 19 and 25 weeks of age. Murine PSCA was strongly expressed on approximately 60% of the cells of TRAMP tumors, at an age where the number of PSCA+ cells and the level of expression of PSCA is very low in the normal prostate. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) +/- mice develop a number of different cancers, including prostate cancer. The incidence of prostate cancer is low and occurs after a relatively long latency. Fluorescence-activated cell sorter analysis of prostatic tissue from 11-18-month-old PTEN +/- mice showed elevated numbers of PSCA+ cells in the prostate, and immunohistochemical analysis showed high mPSCA expression in the tumors of these mice. Together, these results show that two distinct mechanisms of carcinogenesis lead to expression of a common target antigen.
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PMID:Alternative pathways to prostate carcinoma activate prostate stem cell antigen expression. 1130 75

The tumor suppressor gene PTEN (phosphatase and tensin homologue deleted from chromosome 10) encodes a dual specific protein and phospholipid phosphatase that affects cell proliferation, apoptosis and migration. In our study, we examined protein expression of PTEN in renal carcinogenesis. PTEN protein levels were examined in 42 clear cell renal cell carcinomas (ccRCC) and oncocytomas as well as in the corresponding normal renal tissue of the same patients using Western blot analysis. Cellular localization was analyzed by immunohistochemistry. PTEN was highly expressed in all investigated normal renal tissue specimens. Immunohistochemical analysis showed an almost exclusive staining of proximal tubulus epithelial cells known to be precursor cells of ccRCC. Within the proximal tubulus cells, PTEN exhibited a membrane predominant immunostaining pattern. In ccRCCs PTEN expression was markedly reduced to an average of less than 10% compared with normal tissue as evidenced by Western blot analysis (p < 0.001). The degree of reduction was similar in highly differentiated (G1) carcinomas and in less differentiated (G2-G4) carcinomas. These observations were reproduced by immunohistochemical studies, which revealed a loss of the characteristic membrane predominant immunostaining pattern in ccRCC. In contrast to the PTEN positive proximal tubulus epithelial cells, the distal tubulus epithelial cells, which are precursor cells of the benign oncocytomas, exhibited only a very weak PTEN expression. Compared with the distal tubulus epithelial cells, no downregulation of PTEN was seen in oncocytomas. We conclude that PTEN expression and PTEN membrane localization are lost during early renal cell carcinogenesis and may therefore be a valuable RCC tumor marker.
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PMID:Loss of tumor suppressor protein PTEN during renal carcinogenesis. 1194 91

PTEN (phosphatase and tensin homologue deleted on chromosome 10) and p53 alterations were expected to be diversely involved in endometrial carcinogenesis. Patients (n=92) with endometrial carcinoma (EC) were analyzed, and PTEN and p53 were immunostained in the tissue sections. Tumor histology, grade of differentiation, presence of endometrial hyperplasia, staining status of PTEN and p53 and clinical information were examined. There were 37 cases (40%) negative for PTEN staining, which suggests lost or reduced PTEN function. Loss of PTEN staining was significantly related to the advanced staging in the grade 1 (G1) and grade 2 (G2) endometrioid adenocarcinoma group (p=0.026). Also, 18 cases (20%) showed positive staining for p53. p53 staining was largely found in grade 3 (G3) endometrioid adenocarcinoma and other phenotypes of EC. In the G1 and G2 group, all 29 cases with reduced PTEN staining showed p53-negative staining (p=0.025). In the G3 and others group, 6 of 8 cases with reduced PTEN staining showed p53-positive staining. p53-positive staining was associated with a high probability of tumor recurrence in the G1 and G2 group (p=0.0234). In contrast, in the G3 and others group, p53-positive cases had a low probability of tumor recurrence (p=0.0473). Both PTEN and p53 staining may be good indicators of clinical stage and probability of tumor recurrence in EC. Reciprocal abnormality of p53 or PTEN occurred at an early phase of carcinogenesis, however simultaneous abnormality of p53 and PTEN often occurred at the a late phase of carcinogenesis. Thus, immunohistochemistry for PTEN and p53 in biopsy specimens of EC can provide supportive information for determining a treatment plan.
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PMID:PTEN and p53 abnormalities are indicative and predictive factors for endometrial carcinoma. 1558 96

Methylselenol has been implicated as an active metabolite for the anticancer effect of selenium in part through the induction of cancer cell apoptosis. Since inactivation of the AKT/protein kinase B negative regulator gene PTEN (phosphatase and tensin homologue deleted on chromosome 10) is common in prostate cancer (PCa), we compared PTEN wild-type DU145 PCa cells (low basal AKT activity) with PTEN-mutant LNCaP PCa cells (high basal AKT activity) for their apoptosis responses to the methylselenol precursor methylseleninic acid (MSeA) and sodium selenite, an inorganic salt. Our results show that LNCaP cells withstood approximately 4 times higher doses of MSeA than DU145 cells, although they were slightly more sensitive than the latter to selenite-induced apoptosis. Treatment by MSeA modestly attenuated AKT phosphorylation and increased phospho-ERK1/2 in LNCaP cells. Selenite treatment increased the phosphorylation of p53 Ser15 and both kinases, but the selenite-induced apoptosis was not influenced by chemical inhibitors of either kinase. In contrast, PI3K/AKT inhibitors greatly sensitized LNCaP cells to apoptosis induced by MSeA, accompanied by increased mitochondrial release of cytochrome c and multiple caspase activation without changing p53 Ser15 phosphorylation. The apoptosis was further accentuated by extracellular signal regulated kinases 1 and 2 (ERK1/2) inhibition without further increase in cytochrome c release. The general caspase inhibitor z-VAD-fmk completely blocked MSeA-induced apoptosis when both kinases were inhibited, whereas a caspase-8 inhibitor exerted a greater protection than did a caspase-9 inhibitor. Transfection of DU145 cells with a constitutively active AKT increased their resistance to MSeA-induced apoptosis. In summary, AKT played an important role in regulating apoptosis sensitivity of LNCaP and DU145 cells to MSeA. An MSeA-induced activation of ERK1/2 in LNCaP cells also contributed to resistance to apoptosis. However, these kinases did not significantly regulate caspase-mediated apoptosis induced by selenite in LNCaP cells. These findings support the differential involvement of these protein kinase pathways in regulating apoptosis induction by different forms of selenium.
Carcinogenesis 2005 Aug
PMID:PKB/AKT and ERK regulation of caspase-mediated apoptosis by methylseleninic acid in LNCaP prostate cancer cells. 1584 51

Phosphatase and tensin homologue deleted on chromosome 10 (PTEN), a tumor suppressor phosphatase that dephosphorylates both protein and lipid substrates, is found to be mutated in both heritable and sporadic breast cancer. Cellular PTEN has been shown to regulate Akt phosphorylation, mitogen-activated protein kinase (MAPK) phosphorylation, p27(kip1), and cyclin D1 protein levels. Additionally, we and others have shown that PTEN can regulate not only the cell cycle but also cellular apoptosis. Until recently, the functions of PTEN have been thought to occur through cytoplasmic PTEN. However, we have shown that PTEN localizes to the nucleus and that this localization coincides with the G0-G1 phases of the cell cycle. Furthermore, we have shown that PTEN has bipartite nuclear localization sequence (NLS)-like sequences that are required for major vault protein-mediated nuclear import. These findings suggest that subcellular localization of PTEN may regulate its function and that nuclear-localized PTEN may regulate unique cellular functions that have been attributed to cytoplasmic PTEN. To examine this possibility, we analyzed downstream PTEN readouts using MCF-7 Tet-Off breast cancer cell lines stably transfected with two different NLS mutant PTEN constructs, which do not localize to the nucleus, and compared these with cells transfected with wild-type PTEN and empty vector control cells. We found that cytoplasmic PTEN down-regulates phosphorylation of Akt and up-regulates p27(kip1), whereas nuclear PTEN down-regulates cyclin D1 and prevents the phosphorylation of MAPK. Additionally, whereas we observe that nuclear PTEN is required for cell cycle arrest, we found that cytoplasmic PTEN is required for apoptosis. Our observations show that nuclear-cytoplasmic partitioning differentially regulates the cell cycle and apoptosis and, in this manner, provide further evidence that nuclear import of PTEN should play a role in carcinogenesis.
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PMID:Nuclear-cytoplasmic partitioning of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) differentially regulates the cell cycle and apoptosis. 1616 82

There is considerable debate whether peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) ligands potentiate or suppress colon carcinogenesis. Whereas administration of a PPARbeta ligand causes increased small intestinal tumorigenesis in Apc(min/+) mice, PPARbeta-null (Pparb-/-) mice exhibit increased colon polyp multiplicity in colon cancer bioassays, suggesting that ligand activation of this receptor will inhibit colon carcinogenesis. This hypothesis was examined by treating wild-type (Pparb+/+) and Pparb-/- with azoxymethane, coupled with a highly specific PPARbeta ligand, GW0742. Ligand activation of PPARbeta in Pparb+/+ mice caused an increase in the expression of mRNA encoding adipocyte differentiation-related protein, fatty acid-binding protein, and cathepsin E. These findings are indicative of colonocyte differentiation, which was confirmed by immunohistochemical analysis. No PPARbeta-dependent differences in replicative DNA synthesis or expression of phosphatase and tensin homologue, phosphoinositide-dependent kinase, integrin-linked kinase, or phospho-Akt were detected in ligand-treated mouse colonic epithelial cells although increased apoptosis was found in GW0742-treated Pparb+/+ mice. Consistent with increased colonocyte differentiation and apoptosis, inhibition of colon polyp multiplicity was also found in ligand-treated Pparb+/+ mice, and all of these effects were not found in Pparb-/- mice. In contrast to previous reports suggesting that activation of PPARbeta potentiates intestinal tumorigenesis, here we show that ligand activation of PPARbeta attenuates chemically induced colon carcinogenesis and that PPARbeta-dependent induction of cathepsin E could explain the reported disparity in the literature about the effect of ligand activation of PPARbeta in the intestine.
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PMID:Ligand activation of peroxisome proliferator-activated receptor beta inhibits colon carcinogenesis. 1661 65

Ultraviolet A (UVA, 315-400 nm), constituting about 95% of ultraviolet irradiation in natural sunlight, represents a major environmental challenge to the skin and is clearly associated with human skin cancer. It has proven difficult to show direct actions of UVA as a carcinogen in human cells. Here, we demonstrate that chronic UVA exposures at environmentally relevant doses in vitro can induce malignant transformation of human keratinocytes associated with acquired apoptotic resistance. As evidence of carcinogenic transformation, UVA-long-treated (24 J/cm(2) once/week for 18 weeks) HaCaT (ULTH) cells showed increased secretion of matrix metalloproteinase (MMP-9), overexpression of keratin 13, altered morphology and anchorage-independent growth. Malignant transformation was established by the production of aggressive squamous cell carcinomas after inoculation of ULTH cells into nude mice (NC(r)-nu). ULTH cells were resistant to apoptosis induced not only by UVA but also by UVB and arsenite, two other human skin carcinogens. ULTH cells also became resistant to apoptosis induced by etoposide, staurosporine and doxorubicin hydrochloride. Elevated phosphorylation of protein kinase B (PKB, also called AKT) and reduced expression of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) were detected in ULTH cells. The resistance of ULTH cells to UVA-induced apoptosis was reversed by either inhibition of phosphatidylinositol 3-kinase (PI-3K) or adenovirus expression of PTEN or dominant negative AKT. These data indicate that UVA has carcinogenic potential in human keratinocytes and that the increased AKT signaling and decreased PTEN expression may contribute to this malignant transformation. Further comparisons between the transformed ULTH and control cells should lead to a better understanding of the mechanism of UVA carcinogenesis and may help identify biomarkers for UVA-induced skin malignancies.
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PMID:Chronic UVA irradiation of human HaCaT keratinocytes induces malignant transformation associated with acquired apoptotic resistance. 1668 58

Recently, it has been shown that mice deficient in the proapoptotic protein prostate apoptosis response 4 (Par-4) are specifically prone to develop endometrial carcinomas. Based on this, we have examined here the possible role of Par-4 as a tumor suppressor gene in human endometrial cancer. Using cDNA arrays, quantitative reverse transcription-PCR, and immunohistochemistry, we detected Par-4 down-regulation in approximately 40% of endometrial carcinomas. This alteration was not associated with phosphatase and tensin homologue (PTEN), K-RAS, or beta-catenin mutations, but was more frequent among tumors showing microsatellite instability (MSI) or among tumors that were estrogen receptor positive. Mutational analysis of the complete coding sequence of Par-4 in endometrial cancer cell lines (n = 6) and carcinomas (n = 69) detected a mutation in a single carcinoma, which was localized in exon 3 [Arg (CGA) 189 (TGA) Stop]. Interestingly, Par-4 promoter hypermethylation was detected in 32% of the tumors in association with low levels of Par-4 protein and was more common in MSI-positive carcinomas. Par-4 promoter hypermethylation and silencing was also detected in endometrial cancer cell lines SKUT1B and AN3CA, and reexpression was achieved by treatment with the demethylating agent 5'-aza-2'-deoxycytidine. Together, these data show that Par-4 is a relevant tumor suppressor gene in human endometrial carcinogenesis.
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PMID:Inactivation of the candidate tumor suppressor par-4 in endometrial cancer. 1733 19

The tumor suppressor protein phosphatase and tensin homologue deleted on chromosome ten (PTEN) plays an important role in intestinal cell proliferation and differentiation and tumor suppression by antagonizing phosphatidylinositol 3-kinase. Despite its importance, the molecular mechanisms regulating PTEN expression are largely undefined. Here, we show that treatment of the colon cancer cell line HT29 with the differentiating agent sodium butyrate (NaBT) increased PTEN protein and mRNA expression and induced c-Jun NH2-terminal kinase (JNK) activation. Inhibition of JNK by chemical or genetic methods attenuated NaBT-induced PTEN expression. In addition, our findings showed a cross-talk between nuclear factor kappaB (NF-kappaB) and JNK with respect to PTEN regulation. Overexpression of the NF-kappaB superrepressor increased PTEN expression and JNK activity, whereas overexpression of the p65 NF-kappaB subunit reduced both basal and NaBT-mediated JNK activation and PTEN expression. Moreover, we showed that overexpression of PTEN or treatment with NaBT increased expression of the cyclin-dependent kinase inhibitor p27(kip1) in HT29 cells; this induction was attenuated by inhibition of PTEN or JNK expression or overexpression of p65. Finally, we show a role for PTEN in NaBT-mediated cell death and differentiation. Our findings suggest that the JNK/PTEN and NF-kappaB/PTEN pathways play a critical role in normal intestinal homeostasis and colon carcinogenesis.
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PMID:Regulation of PTEN expression in intestinal epithelial cells by c-Jun NH2-terminal kinase activation and nuclear factor-kappaB inhibition. 1769 82


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