Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019204 (hepatocellular carcinoma)
 71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A choline non-required cell line was established from a rat hepatoma cell line. The line designated R-Y121B X cho was able to grow in choline-deprived medium without serum and lipid. Choline is necessary for the biosynthesis of phosphatidylcholine, which is a main component of cell membranes. Phosphatidylcholine can be synthesized by the methylation of phosphatidylethanolamine in liver cells. Phospholipid composition and incorporation of radiolabeled serine into phosphatidylserine or phosphatidylethanolamine were quite similar in R-Y121B X cho and its parental cells. However R-Y121B X cho cells had higher phosphatidylcholine synthesis activity from radiolabeled methionine than parental cells. These results indicate that choline requirement of mammalian cells depends on the activity of phosphatidylethanolamine methyltransferase.
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PMID:Continuous growth and phosphatidylcholine synthesis of rat hepatoma cells in choline-deprived chemically defined medium. 393 May 27

The expression of rat liver phosphatidylethanolamine N-methyltransferase-2 (PEMT2) in McA-RH7777 rat hepatoma cells resulted in the unexpected inhibition of cell growth. There was a strict correlation (r = 0.973) between the level of expression of the enzyme activity and the generation time for hepatoma cell division. Expression of other foreign proteins via the same vector did not inhibit McA-RH7777 cell growth; thus, retardation of cell division was specific for the methyltransferase. Addition of 1 microM 3-deazaadenosine, which causes inhibition of phosphatidylethanolamine methylation, reversed the PEMT2-mediated inhibition of cell division. Transfection of a line of Chinese hamster ovary cells with PEMT2 had no effect on the division of these cells. Induction of hepatic tumors in rats with N-nitrosodiethylamine coincided with a striking decrease in methyltransferase activity and immunoreactive protein in the tumor nodules. Thus, data from studies in cell culture and intact rats suggest a regulatory role for PEMT2 in hepatocyte cell growth and possibly in the development of liver cancer.
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PMID:Suppression of rat hepatoma cell growth by expression of phosphatidylethanolamine N-methyltransferase-2. 792 20

Phosphatidylethanolamine N-methyltransferase catalyzes the synthesis of phosphatidylcholine from phosphatidylethanolamine and is most active in liver. A cDNA for this enzyme from a rat liver cDNA library has been cloned, sequenced, and expressed in COS-1 cells, McArdle-RH7777 rat hepatoma cells, and Sf9 insect cells. The expressed protein was capable of converting phosphatidylethanolamine into phosphatidylcholine in intact COS-1 cells, which normally have very low methyltransferase activity. The calculated molecular mass of the methyltransferase protein is 22.3 kDa, which is equivalent to that of the pure protein isolated from rat liver. Comparison of the sequence of the cloned rat liver methyltransferase with the yeast phosphatidylethanolamine methyltransferase PEM2 gene product revealed 44% identical amino acids and 68% similarity in the two predicted protein sequences. A polyclonal antibody was raised against a synthetic peptide corresponding to the carboxyl-terminal region of the enzyme and was affinity purified. The antibody recognized a single protein with a molecular mass of approximately 20 kDa when either rat liver proteins or proteins derived from the transfected COS-1 cells were electrophoresed on polyacrylamide gels containing sodium dodecyl sulfate. Surprisingly, the antibody exhibited no reactivity with endoplasmic reticulum proteins, even though the major phosphatidylethanolamine methyltransferase activity resides on this subcellular organelle. Instead, the antibody specifically recognized a protein in a unique subcellular membrane fraction purified from a crude mitochondrial preparation on a Percoll gradient. Immunocytochemical examination by electron microscopy showed positive labeling only in unique regions of the hepatocytes. The data suggest that this phosphatidylethanolamine methyltransferase is a specific marker for this unique membrane fraction.
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PMID:Cloning and expression of a novel phosphatidylethanolamine N-methyltransferase. A specific biochemical and cytological marker for a unique membrane fraction in rat liver. 834 45

Phosphatidylethanolamine N-methyltransferase-2 (PEMT2) of rat liver was expressed in McArdle-RH7777 rat hepatoma cells, which lack endogenous PEMT activity. Expression of the enzyme was confirmed by assay of PEMT activity and immunoblotting. There was no change in the amount of phosphatidylcholine in the transfected cells [Cu, Houweling and Vance (1994) J. Biol. Chem. 269, 24531-24533], even though the expression of PEMT2 caused an increased incorporation of [methyl-3H]methionine and [3H]ethanolamine into phosphatidylcholine. In contrast, [3H]serine incorporation into phosphatidylcholine was only marginally enhanced by PEMT2 expression. Incorporation of [methyl-3H]choline into phosphatidylcholine was decreased by greater than 60%, suggesting that the CDP-choline pathway was inhibited as a result of PEMT2 expression. CTP:phosphocholine cytidylyltransferase (CT) activities in transfected cell lines were decreased in proportion to the level of expression of PEMT2. Immunoblot analyses showed a decrease in CT mass as a function of PEMT2 expression. In contrast, there was no change in the mass of protein disulphide-isomerase or the relative amounts of most proteins expressed in the PEMT2-transfected, compared with control, cells. Similarly, the expression of CT mRNA was decreased in PEMT2-expressing cells, whereas the mRNAs for protein disulphide-isomerase and actin were unchanged. When cell growth was slowed by incubating McArdle-RH7777 cells at 25 degrees C, compared with 37 degrees C, there was no difference in the specific activity of the CT. These results argue that PEMT2 expression down-regulates the CDP-choline pathway by decreasing the expression of the gene for the CT. The decreased activity of the CDP-choline pathway might contribute to the slower rate of cell division in PEMT2-transfected hepatoma cells.
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PMID:Expression of phosphatidylethanolamine N-methyltransferase-2 in McArdle-RH7777 hepatoma cells inhibits the CDP-choline pathway for phosphatidylcholine biosynthesis via decreased gene expression of CTP:phosphocholine cytidylyltransferase. 855 42

Phosphatidylethanolamine is converted to phosphatidylcholine in hepatocytes via the enzyme phosphatidylethanolamine N-methyltransferase (PEMT). An isoform, PEMT2 has been cloned, expressed and localized to a mitochondria-associated membrane in rat liver. Expression of PEMT2 caused a decreased rate of cell division of cultured rat hepatoma cells. Mechanistic studies suggest that the slower growth of transfected hepatoma cells may be due to down regulation of CTP: phosphocholine cytidylyltransferase and the CDP-choline pathway for phosphatidylcholine biosynthesis. A role for PEMT2 in the regulation of hepatocyte cell division is also indicated by PEMT2 down-regulation in regenerating rat liver.
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PMID:Phosphatidylethanolamine methylation and hepatoma cell growth. 869 9

Expression of phosphatidylethanolamine N-methyltransferase (PEMT)-2 in rat hepatoma cells caused an increase in the time for cell division from 18 to 50 h [Cui et al. (1994) J. Biol. Chem. 269, 24531-24533]. We investigated whether or not a similar inverse relationship might exist for liver proliferation in vivo. Thus, partial hepatectomized rats were used to investigate the expression of PEMT2 during liver regeneration. Enhanced biosynthesis of phosphatidylcholine after partial hepatectomy was due to increased activity and amount of CTP:phosphocholine cytidylyltransferase. On the other hand the total activity of PEMT was markedly decreased during the first days of rat liver regeneration. Maximal decrease of total PEMT activity (45%) and loss of PEMT2 protein (90%) coincided with maximal DNA synthesis and CTP:phosphocholine cytidylyltransferase activity 24 h after partial hepatectomy in both male and female rats. Supplementing dietary choline in the diets of female rats shifted this pattern from 24 h to 36 h after partial hepatectomy, whereas the pattern in male rats was not affected. Northern blot studies showed that the amount of PEMT2 mRNA was decreased accordingly, suggesting regulation of the amount and activity of PEMT2 at a pre-translational level. Thus, our data show a reciprocal regulation of CTP:phosphocholine cytidylyltransferase and PEMT2 at the level of gene expression in regenerating rat liver. These results implicate PEMT2 in the regulation of hepatocyte cell growth in a physiologically relevant model.
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PMID:Induction of hepatocyte proliferation after partial hepatectomy is accompanied by a markedly reduced expression of phosphatidylethanolamine N-methyltransferase-2. 918 96

Our previous studies have implicated the liver-specific phosphatidylethanolamine N-methyltransferase-2 (PEMT2) in suppression of hepatocarcinoma proliferation (Cui et al. (1994) J. Biol. Chem. 269, 24531-24533). It was not known if this phenomenon in cell culture had relevance to liver growth and PEMT2 expression in an intact animal. Hence, we investigated the relationship between normal proliferation of liver and the expression of PEMT2 during the perinatal period of developing rats. PEMT2 protein was completely absent, and PEMT activity was very low, in prenatal livers in which liver growth is rapid. At birth, a decrease of liver growth coincided with the rapid appearance in liver of a high level of PEMT2 protein that was sustained throughout adult life. Northern blots revealed that the postnatal expression of PEMT2 correlated with the level of its mRNA. Immunohistochemical staining of liver sections showed a distinctive pattern of PEMT2 expression at birth. A high level of PEMT2 was expressed in defined extranuclear regions of hepatocytes from newborn rats whereas the protein was dispersed in the extranuclear areas in adult hepatocytes. The inverse correlation between the rate of liver growth and PEMT2 expression together with other results suggest that this enzyme, or its product, is involved in control of normal liver proliferation.
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PMID:Inverse correlation between expression of phosphatidylethanolamine N-methyltransferase-2 and growth rate of perinatal rat livers. 918 97

Phosphatidylethanolamine is converted to phosphatidylcholine in mammalian liver by the enzyme phosphatidylethanolamine N-methyltransferase (PEMT). A form of the enzyme (PEMT2) has been isolated from rat liver, the cDNA cloned and expressed and the murine gene has been characterized and disrupted. Several lines of evidence suggested that PEMT2 might have a role in hepatocyte proliferation and liver cancer. Hence, we decided to investigate the human form of the enzyme. Unexpectedly, we cloned and expressed three novel human cDNAs encoding PEMT2. These forms differ from each other in the 5'-region with the point of divergence being 15 nucleotides upstream of the putative translation initiation codon. The remainder of the three cDNAs was identical. Expression of the coding region of the cDNAs in McArdle rat hepatoma cells resulted in three stable cell lines that showed a 27- to 115-fold elevation of PEMT activity compared to vector-transfected control cell lines. Screening of somatic cell hybrid panels, radiation hybrid panel mapping and fluorescent in situ hybridization mapping localized the human gene for PEMT2 to chromosome 17p11.2. The identification of three different human cDNAs for PEMT2 suggests that understanding the function of PEMT2 will be more complicated than anticipated.
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PMID:Identification of three novel cDNAs for human phosphatidylethanolamine N-methyltransferase and localization of the human gene on chromosome 17p11.2. 998 71

Previous studies have implicated phosphatidylethanolamine N-methyltransferase-2 (PEMT2) in the regulation of non-neoplastic liver growth [Tessitore,L., Cui,Z. and Vance,E. (1997) Biochem. J., 322, 151-154]. We have now investigated whether or not PEMT2 is also involved in the control of proliferation of hepatoma cells growing in an animal and cell death by apoptosis in the liver of tumor-bearing rats. PEMT activity was barely detectable and PEMT2 protein was absent in hepatoma cells growing exponentially in vivo whereas CTP:phosphocholine cytidylyltransferase (CT) activity and expression were high. The lack of PEMT2 corresponded with the absence of its mRNA. Both PEMT2 protein and mRNA appeared when cells entered the stationary phase of tumor growth and, in parallel, CT expression decreased. The host liver first became hyperplastic and exhibited a slight increase in CT activity and decrease in PEMT2 expression. During the stationary phase of hepatoma growth the host liver regressed and eventually became hypoplastic following induction of apoptosis. The appearance of apoptosis in the host liver was associated with a marked reduction in both CT activity and expression as well as an enhancement of PEMT activity and PEMT2 expression. McArdle RH7777 hepatoma cells underwent apoptosis when transfected with cDNA for PEMT2. The evidence supports the proposal that PEMT2 may have a role in the regulation of 'in vivo' hepatoma and hepatocyte cell division as well as hepatocyte cell death by apoptosis.
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PMID:Expression of phosphatidylethanolamine N-methyltransferase in Yoshida ascites hepatoma cells and the livers of host rats. 1022 82

Much progress has been made in the understanding of the pathogenesis of alcoholic liver disease, resulting in improvement of treatment. Therapy must include correction of nutritional deficiencies, while taking into account changes of nutritional requirements. Methionine is normally activated to S-adenosylmethionine (SAMe). However, in liver disease, the corresponding enzyme is depressed. The resulting deficiencies can be attenuated by the administration of SAMe but not by methionine. Similarly, phosphatidylethanolamine methyltransferase activity is depressed, but the lacking phosphatidylcholine (PC) can be administrated as polyenylphosphatidylcholine (PPC). Chronic ethanol consumption increases CYP2E1, resulting in increased generation of toxic acetaldehyde and free radicals, tolerance to ethanol and other drugs, and multiple ethanol-drug interactions. Experimentally, PPC opposes CYP2E1 induction and fibrosis. Alcoholism and hepatitis C infection commonly co-exist, with acceleration of fibrosis, cirrhosis, and hepatocellular carcinoma. PPC is being tested clinically as a corresponding antifibrotic agent. Available antiviral agents are contraindicated in the alcoholic. Anti-inflammatory agents, such as steroids, may be selectively useful. Finally, anticraving agents, such as naltrexone or acamprosate, should be part of therapy.
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PMID:Liver diseases by alcohol and hepatitis C: early detection and new insights in pathogenesis lead to improved treatment. 1126 19


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