Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1326912 (tumorigenesis)
 57,481 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A total 39 kidney tumors were induced by a continuous oral administration of N-butylnitrosourea (BNU) in 33 out of 204 rats of W/Fu strain and of 41 (W/Fu X ACI/N)F1 rats. No spontaneous renal tumors were observed among 66 males and 109 females of W/Fu rats which survived beyond the age of 19 months. Histologically, renal cell and mesenchymal types were commonly observed; 24 cases belonging to the former and 11 cases to the latter. Two cases of nephroblastoma were also encountered. There was no sex difference in renal tumorigenesis with BNU as a whole. Castration in both sexes was apparently inhibitory for kidney tumor development. Estrogenization of castrated rats either by syngeneic ovary graft or by repeated injections of estradiol benzoate enhanced tumor induction with BNU. Progesterone was not effective in restoring the tumor incidence in castrated rats. Distribution of histological types of tumors thus induced differed among the hosts with different hormonal conditions; in males the majority was renal cell type, whereas almost all mesenchymal tumor and nephroblastoma cases were found in intact females or estrogenized rats. BNU induced a variety of tumors in several organs including cerebral hemisphere, peripheral nerves, mammary glands, hematopoietic system, digestive tracts, and so on. However, such concurrence did not affect the development of renal tumors in the present study.
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PMID:Influence of sex hormones on kidney tumors induced in rats with N-butylnitrosourea. 17 65

An altered pattern of cytochrome P-450-dependent microsomal steroid metabolism was identified in female mouse liver tumors induced by 5,9-dimethyldibenzo[c,g]carbazole, a potent organo-specific liver carcinogen. These tumor tissues were compared to extratumoral liver parenchyme, to normal, fetal and neonatal livers and to spontaneous liver tumors, the frequency of which is very low in the highly hybridized mouse strain (XVIInc/Z) used for liver tumorigenesis. Cytochrome P-450-dependent steroid hydroxylase activities were measured by the identification and quantification of four monohydroxyprogesterone and eight monohydroxytestosterone metabolites. In contrast to a general decrease (50%) of total P-450 in tumor microsomes, the individual steroid hydroxylases were regulated differently. Progesterone 16 alpha- and testosterone 6 alpha-, 6 beta-, 7 alpha- and 16 alpha-hydroxylase activities were decreased 50%, and more, whereas progesterone and testosterone 15 alpha-hydroxylase activities were raised 3-4 times with regard to microsomal protein content and 6-7 times with regard to total P-450. Consequently the most prominent feature of the steroid metabolism by tumor-borne microsomes is the hydroxylation at the 15 alpha-position. Furthermore, minor testosterone 2- and 15 beta-hydroxylase activities showed equally an increase of approximately 4 times (8 times with regard to total P-450). The observed new tumoral pattern of P-450-dependent microsomal steroid metabolism appearing characteristically in spontaneous and chemically induced liver tumors indicates that particular P-450 enzymes are strongly expressed in mouse liver tumors. These enzymes may be used as markers for early stages in liver tumorigenesis.
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PMID:Particular cytochrome P-450-dependent steroid metabolism: a new class of mouse liver tumor markers. 279 Dec 5

The protective effect of progesterone on the development of chemically induced carcinomas (squamous cell carcinomas in mice and basal cell carcinomas in rats) by 3-methylcholanthrene [(MCA) CAS: 56-49-5] was studied. Progesterone administration decreased the average number, size, and weight of carcinomas by 45-50% as compared to those of tumors treated with MCA alone at any time interval. DNA radioactivity and autoradiographic studies with the use of [3H]thymidine showed an inhibition of DNA synthesis in the neoplastic cell nuclei following a concomitant administration of progesterone and MCA (18.4%) as compared to the DNA synthesis following administration of MCA alone (35.0%). Electron microscopic and cytologic observations revealed salient ultrastructural findings following progesterone administration, with advanced cytolysis, tumefied mitochondria, large populations of secondary lysosomes, and autophagic formations; also, cell differentiation tended to be of a glandular-adenomatoid type following progesterone and MCA administration as compared to the characteristic squamous cell and basal cell carcinomas after treatment with MCA alone. In addition, scanning electron microscopic observations revealed advanced cytolytic areas with several disintegrated neoplastic cells and cell debris intermingled with red blood cells, following progesterone and MCA administration. The present findings demonstrate that progesterone in pharmacologic doses exerts important chemoprotective effects on carcinoma formation, possibly by interfering with MCA metabolism and inhibiting DNA synthesis in the epidermal neoplastic cells, and thus plays an important role in tumorigenesis.
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PMID:Chemoprotective effect of progesterone on carcinoma formation in mice and rats. 385 56

To evaluate the possible involvement of the salivary glands in the modulation of medroxyprogesterone (MPA)-induced mammary tumorigenesis, 48 sialoadenectomized virgin BALB/c female mice and 47 controls were treated with 40mg MPA depot s.c. every 3 months for 1 year. Mammary tumors developed in 11 sialoadenectomized and in 34 control mice with similar latencies. In both groups, 75% of the tumors were ductal and progestin-dependent (PD) while the remainder were lobular and progestin-independent (PI). Epidermal growth factor (EGF) levels were measured in salivary glands (SG-EGF) and serum (S-EGF) in both groups. MPA induced a significant increase in SG-EGF and in S-EGF that became evident only after 1 month of MPA treatment. No increase in S-EGF was detected in MPA-treated sialoadenectomized mice, indicating that salivary glands are the major source of S-EGF. The presence of EGF receptors (EGF-R) was investigated in ductal PD and PI tumor lines and compared with 8 PI tumor lines of lobular origin. A significant difference in EGF-R content was found between lobular and ductal tumors. No increase in EGF-R was noted when ductal tumors became autonomous. EGF-R did not correlate with tumor growth rate and there was an inverse correlation between EGF-R and steroid receptors. When the effect of sialoadenectomy on tumor growth was tested in vivo in syngeneic transplants of 2 ductal PD, 1 ductal PI and 2 lobular PI mammary adenocarcinomas, it was not found to be significant when compared with the controls. It may be concluded that SG-EGF plays an important role in the induction of mammary adenocarcinomas by MPA, while it has no significant effect on the growth of established tumors.
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PMID:Effect of sialoadenectomy on medroxyprogesterone-acetate-induced mammary carcinogenesis in BALB/c mice. Correlation between histology and epidermal-growth-factor receptor content. 792 19

Hepatitis B virus produces a small (154-amino acid) transcriptional transactivating protein, HBx, which is required for viral infection and has been implicated in virus-mediated liver oncogenesis. However, the molecular mechanism for HBx activity and its possible influence on cell proliferation have remained obscure. A number of studies suggest that HBx may stimulate transcription by indirectly activating transcription factors, possibly by influencing cell signaling pathways. We now present biochemical evidence that HBx activates Ras and rapidly induces a cytoplasmic signaling cascade linking Ras, Raf, and mitogen-activated protein kinase (MAP kinase), leading to transcriptional transactivation. HBx strongly elevates levels of GTP-bound Ras, activated and phosphorylated Raf, and tyrosine-phosphorylated and activated MAP kinase. Transactivation of transcription factor AP-1 by HBx is blocked by inhibition of Ras or Raf activities but not by inhibition of Ca(2+)- and diacylglycerol-dependent protein kinase C. HBx was also found to stimulate DNA synthesis in serum-starved cells. The hepatitis B virus HBx protein therefore stimulates Ras-GTP complex formation and promotes downstream signaling through Raf and MAP kinases, and may influence cell proliferation.
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PMID:Hepatitis B virus HBx protein activates Ras-GTP complex formation and establishes a Ras, Raf, MAP kinase signaling cascade. 793 54

In previous papers we have demonstrated that sialoadenectomy inhibited MPA-induced mammary tumorigenesis in BALB/c mice. To further explore the role of EGF in this experimental model, we evaluated its effects on mammary glands of sialoadenectomized (sialox) MPA-treated female mice and on tumor growth. MPA-treated sialox mice were injected s.c. (n = 3) or not (n = 6) with 5 microg EGF every 36 h for 45 days; MPA-treated sham-operated mice were used as controls (n = 6). Mammary glands from sialox MPA-treated mice are considerably less developed as compared with sham-operated animals. The exogenous administration of EGF restores the usual MPA-induced growth pattern of the glands, thus confirming a role for EGF either in mediating or cooperating with MPA in inducing the mammary architectural changes observed in MPA-treated mice. On the other hand, primary cultures of progestin-dependent (PD) ductal mammary adenocarcinoma in vivo tumor lines and of lobular progestin-independent (PI) tumor lines were used to evaluate the effect of EGF on tumor growth. In vitro EGF was found to stimulate cell proliferation of lobular PI tumor cells and of fibroblastic cells from both types of tumors at concentrations higher than 0.1-0.5 ng/ml and in the presence of 1-5% of charcoal-stripped fetal calf serum. Conversely, no proliferative effects were observed in ductal PD cells under the same experimental conditions, regardless of the presence of 10 nM MPA. It can be concluded that although EGF plays an important role in MPA-induced mammary carcinogenesis, it is not necessary in PD tumor growth.
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PMID:Involvement of EGF in medroxyprogesterone acetate (MPA)-induced mammary gland hyperplasia and its role in MPA-induced mammary tumors in BALB/c mice. 956 48

Progesterone plays a central coordinate role in regulating reproductive events associated with the establishment and maintenance of pregnancy including ovulation, uterine and mammary gland development and tumorigenesis, and neurobehavioral expression associated with sexual responsiveness. The effects of progesterone are mediated by two receptor proteins (PR), termed A and B, that arise from a single gene and act as ligand-activated transcription factors to regulate the expression of reproductive target genes. Null mutation of both proteins in mice leads to pleiotropic reproductive abnormalities. This review summarizes the structure and functional properties of the PR isoforms and how functional differences between these proteins are likely to impact on the overall physiologic role of the receptor in reproductive systems.
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PMID:Reproductive functions of the progesterone receptor. 1073 26

Guanine nucleotides are important substrates for macromolecular synthesis, cell signaling, and integration of metabolic status, and have an evolutionarily conserved role in differentiation, proliferation, and apoptosis. Bacteria, yeast, and mammalian cells are all dependent on an adequate supply of guanylates to maintain proliferation. Depletion of intracellular guanylates, especially by inhibition of de novo synthesis via the IMP dehydrogenase pathway, is a potent signal for inhibition of proliferation, as well as apoptosis. Growth inhibition by depletion of GTP is a conserved pathway from humans to Bacillus. IMPDH expression is downregulated by the p53 tumor suppressor gene. Many inhibitors of IMP dehydrogenase are used as clinical agents. These agents are antivirals (ribavirin), antitumor (tiazofurin [TR], selenazofurin [SR], and benzamide riboside [BR]), and immunosuppressants (mycophenolic acid [MPA]). The biochemical actions of IMP dehydrogenase inhibitors are well known, but correlation with in vivo activities is difficult because the extent of exogenous contributions to the nucleotide metabolic pathways is not fully known. IMPDH inhibitors are biochemically convenient in inhibiting parallel pathways, since excess reactants IMP and 5'-phospho-ribose-1'-pyrophosphate (PRPP) inhibit guanine salvage synthesis. IMPDH activity is a progression-linked key enzyme in tumorigenesis. The antitumor potential of IMPDH inhibitors is therefore particularly high.
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PMID:Molecular targets of guanine nucleotides in differentiation, proliferation and apoptosis. 1095 93

Green tea polyphenols (GTP) have been demonstrated to suppress tumorigenesis in several chemical-induced animal carcinogenesis models, and predicted as promising chemopreventive agents in human. Recent studies of GTP extracts showed the involvement of mitogen-activated protein kinases (MAPKs) in the regulation of Phase II enzymes gene expression and induction of apoptosis. In the current work we compared the biological actions of five green tea catechins: (1) induction of ARE reporter gene, (2) activation of MAP kinases, (3) cytotoxicity in human hepatoma HepG2-C8 cells, and (4) caspase activation in human cervical squamous carcinoma HeLa cells. For the induction of phase II gene assay, (-)-epigallocatechin-3-gallate (EGCG) and (-)-epicatechin-3-gallate (ECG) potently induced antioxidant response element (ARE)-mediated luciferase activity, with induction observed at 25 microM with EGCG. The induction of ARE reporter gene appears to be structurally related to the 3-gallate group. Comparing the activation of MAPK by the five polyphenols, only EGCG showed potent activation of all three MAPKs (ERK, JNK and p38) in a dose- and time-dependent manner, whereas EGC activated ERK and p38. In the concentration range of 25 microM to 1 mM, EGCG and ECG strongly suppressed HepG2-ARE-C8 cell-growth. To elucidate the mechanisms of green tea polyphenol-induced apoptosis, we measured the activation of an important cell death protein, caspase-3 induced by EGCG, and found that caspase-3 was activated in a dose- and time-dependent manner. Interestingly, the activation of caspase-3 was a relatively late event (peaked at 16 h), whereas activation of MAPKs was much earlier (peaked at 2 h). It is possible, that at low concentrations of EGCG, activation of MAPK leads to ARE-mediated gene expression including phase II detoxifying enzymes. Whereas at higher concentrations of EGCG, sustained activation of MAPKs such as JNK leads to apoptosis. These mechanisms are currently under investigation in our laboratory. As the most abundant catechin in GTP extract, we found that EGCG potently induced ARE-mediated gene expression, activated MAP kinase pathway, stimulated caspase-3 activity, and induced apoptosis. These mechanisms together with others, may contribute to the overall chemopreventive function of EGCG itself as well as the GTP
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PMID:Activation of antioxidant-response element (ARE), mitogen-activated protein kinases (MAPKs) and caspases by major green tea polyphenol components during cell survival and death. 1115 83

Drm/Gremlin, a member of the Dan family of BMP antagonists, is known to function in early embryonic development, but is also expressed in a tissue-specific fashion in adults and is significantly downregulated in transformed cells. In this report, we demonstrate that overexpression of Drm in the tumor-derived cell lines Daoy (primitive neuroectodermal) and Saos-2 (osteoblastic), either under ecdysone-inducible or constitutive promoters, significantly inhibits tumorigenesis. Furthermore, Drm overexpression in these cells increases the level of p21(Cip1) protein and reduces the level of phosphorylated p42/44 MAP kinase. Finally, our data indicate that Drm can induce p21(Cip1) transcriptionally via a novel pathway that is independent of p53 and the p38 and p42/44 MAP kinases. These results provide evidence that Drm can function as a novel transformation suppressor and suggest that this may occur through its affect on the levels of p21(Cip1) and phosphorylated p42/44 MAPK.
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PMID:Drm/Gremlin transcriptionally activates p21(Cip1) via a novel mechanism and inhibits neoplastic transformation. 1213 12


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