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J Short

Publications and source records attributed to J Short.

At least 55 records · Page 3Linked to original sources
PubMed1983

Synthesis of an hypothesis advocating a prominent role for the thyroid hormones in mammalian liver cell proliferation in vivo.

This review summarizes the accumulating evidence supporting a conspicuous role for the thyroid hormones and/or hepatic levels of nuclear T3-binding sites in hepatocytes proliferation in vivo. The hepatic nuclear binding sites for the iodothyronines were first described in 1972. Comparing a number of observations made on the hepatic levels of these nuclear T3-binding sites with models of liver cell proliferation, a striking relationship is now beginning to emerge. It seems that in many hepatomitogenic systems the levels of these nuclear binding sites become markedly reduced preceding the onset of enhanced DNA replication and mitosis. The hepatomitogenic systems described which do not involve a lowering in the levels of these nuclear binding sites appear to be predicated on raising the circulating levels of the thyroid hormones per se. How these two seemingly anomalous events can both produce the same proliferative effect on liver cells is not entirely clear. Equally vague as yet are the discrete genetic consequences of these proliferative initiators which lead to hepatocyte hyperplasia. There is some evidence that this proliferative controlling effect on the thyroid hormones on hepatocytes may also extent, in part, to hepatoma cells.

Adrenalectomy↗
PubMed1983

Reciprocal relationship between the levels of the hepatic nuclear binding sites for T3 and DNA replication in the liver of the rat: a possible unifying concept.

Administration of low levels of thyroid hormone (T3), subsequent to adrenalectomy, cause a pronounced proliferative response in rat liver, as judged by enhanced DNA replication. Adrenalectomy of the rat causes a reduction in the maximal nuclear binding capacity for T3 in the liver, similar to that produced by 70% hepatectomy of the rat, the former decrease lagging approximately 12 h after the latter. Similar kinetics are reported for the enhancement of hepatic nuclear DNA synthesis in these two groups of animals. Both of these effects in either group of surgically-treated animals are obviated by the injection of dexamethasone. Other reports are cited indicating that a reciprocal cause-and-effect relationship may exist between the lowering of the hepatic nuclear maximal binding capacity for T3 and subsequent enhanced hepatic DNA replication in a number of other rat model systems. It is suggested that enhanced hepatic cell proliferation in the rat may be effected by either raising the circulating levels of the thyroid hormones or by lowering the levels of the hepatic nuclear binding sites for these agents.

Adrenalectomy↗
PubMed1982

Correlation of circulating levels of a serum protein with triiodothyronine levels and hepatoma growth.

In this communication, we provide evidence that proliferation of transplantable Morris hepatoma 7777 might to some extent be regulated by triiodothyronine and/or a specific serum protein, the levels of which are correlated with levels of triiodothyronine. The protein has an estimated molecular weight of 80,000 and migrates as one band on polyacrylamide gel electrophoresis. In normal rats, this protein accounts for approximately 1% of the total serum protein. Both the circulating levels of the serum protein and proliferating of transplanted hepatoma cells were decreased in thyroidectomized rats. Elevated levels of the serum protein and increased cell proliferation were observed when animals had 70% of their lives removed prior to transplant, were given injections of triiodothyronine, or had a 10-day-old first transplant surgically removed. Some evidence is also provided suggesting that the synthesis of the serum protein is stimulated by thyroid hormone.

Animals↗
PubMed1981

Amounts of triiodothyronine and a serum protein related to hepatic DNA synthesis in the rat.

The increase of a serum protein in the circulation of rats following partial hepatectomy or the injection of thyroid hormone (T3) is reported. This serum protein factor is present in normal rat serum and accounts for approximately 1% of the total serum protein. The protein disappears from the serum of animals bearing Morris hepatomas 7777 or 7800. The amount of serum protein factor diminishes as the tumors increase in size. The levels of this protein in the serum fall immediately following partial hepatectomy. At 24 hours following the operation, however, the levels are increased well over those found in normal rats. Increased levels persist for 12 days following partial hepatectomy. The serum protein is also increased following injections of T3 and is decreased in thyroidectomized animals. Elevated levels of T3 are correlated with elevated levels of the serum protein and both are correlated with increased hepatic DNA synthesis. Low levels of T3 are followed by low levels of serum protein resulting in a diminished capacity for hepatic DNA synthesis. Injection of purified serum factor into normal rats results in increased [3H]thymidine incorporation in liver cells. It is suggested that the synthesis of this serum protein is stimulated by T3 and DNA synthesis is influenced by the serum protein. The serum protein might be a humoral factor influencing metabolic events in hepatocytes or hepatomas or it might be a carrier for an agent that in turn has a direct effect on these tissues.

Animals↗
PubMed1981

The lack of a "pleiotypic response' in hepatocyte proliferation induced in the rat by 3,5,3'-triiodothyronine.

Early morphological and biochemical alterations in proliferatively stimulated liver tissue obtained from 3,5,3'-triiodo-L-thyronine-treated rats were compared to those occurring in the liver remnant of 70% hepatectomized animals, and to controls. Subjecting photographic enlargements of histological slides prepared from these liver tissues to computer-assisted analyses, hepatocyte nuclear and nucleolar volumes were shown to be virtually identical in control and hormone-treated preparations through the first 24 hours after treatment, but significantly different from tissues obtained from partially hepatectomized animals, In vitro estimations of hepatic nuclear RNA polymerase activities early after treatment were also shown to be similar when comparing the hormone- and the saline-treated rats. Estimated by either 3H-orotic acid or 3H-leucine incorporation, the early accumulation of hepatic RNA and liver and serum proteins, significantly enhanced by 70% hepatectomy, were found similar in triiodothyronine-injected and control animals at least through the first 6 h after treatment; hormone administration appeared to cause slight enhancements in these parameters at later prereplicative times. While pharmacological doses (200 micrograms/100g) of the thyroid hormone induce a strong proliferative response in rat liver tissue, only minor prereplicative alterations appear to be elicited in the hepatocytes. This hepatic model offers an important potential tool to investigations aimed at understanding proliferative controls in mammalian liver cells.

Animals↗
PubMed1980

Enhanced hepatic chromatin protein methylation induced by triiodothyronine treatment of the rat.

A pharmacological dose of 3,3',5-triiodo-L-thryonine (200 microgram/100g) that induce marked DNA replication in rat liver cells, also is shown to cause a significant increase in the methylation of chromatin proteins in these cells. This increase in the methylation apppears to correlate with the increase in DNA replication. Specificity of this phenomenon is suggested by its absence in kidney and spleen of the hormone-treated animals, two tissues that also fails to respond proliferatively to the iodothyronine.

Animals↗
PubMed1980

Involvement of the lodothyronines in liver and hepatoma cell proliferation in the rat.

3,3',5-Triiodo-L-thyronine (200 microgram/100 g) is shown to be a potent liver parenchymal cell mitogen in the rat, and thyroidectomy is seen to severely inhibit hepatocyte proliferation in regenerating rat liver. Taken together, these observations point to a crucial role for the iodothyronine in liver cell hyperplasia. The growth rates of the transplantable Morris hepatomas 7777 and 5123tc are shown to be retarded in the surgically thyroidectomized-parathyroidectomized rat. This inhibition of tumor growth can be reversed by thyroid hormone administration. It has earlier been observed that the hypothyroid state induced in the rat by administration of propylthiouracil or radioactive iodine retarded the growth of the transplanted Morris hepatomas 7800 and 44, suggesting that these tumors were also thyroid dependent. Our results suggest that the thyroid hormones may play a similar role in the growth of liver cell-derived cancers as they do in normal hepatocyte proliferation.

Animals↗
PubMed1979

Chromatin protein methylation in proliferating liver and hepatoma cells.

Chromatin protein methylation in proliferating liver cells and hepatomas was examined in vivo and in vitro. Methylation in vivo was estimated using 2-14 C-L-methionine and 3H-methyl-L-methionine. 3H/14C ratios were calculated for crude histone and nonhistone chromatin protein fractions and compared to those calculated for serum albumin. From this, determination of a methylation index was calculated using serum albumin as a standard. Results of this study indicate that both histones and nonhistone chromatin proteins are methylated to a greater extent in proliferating liver cells and in hepatomas than in control preparations. These observations are generally supported by our in vitro methylation studies. The results are discussed in terms of chromatin protein methylation and its possible relationship to DNA replication.

Animals↗
PubMed1976

Amino acids and control of nucleolar size, the activity of RNA polymerase I, and DNA synthesis in liver.

The volume of nucleolar material per nucleus and the activity of RNA polymerase I (RNA nucleotidyltransferase I) become doubled in the liver cells of rats that are fed for several days a diet that lacks essential amino acids. Omission of methionine from a fully supplemented diet is equivalent to leaving out all the amino acids, and the responses to a deficiency of tryptophan are about 40% as great. Deprivation of one of the remaining essential amino acids gives either small responses or none at all. Supplementation of the methionine-free diet with cystine blocks the nucleolar enlargement and the enhancement of the polymerase activity that would otherwise take place, but the dispensable amino acid does not affect the responses to a deprivation of one of the other essential amino acids. After deprivation of all the essential amino acids or only methionine, hepatocytes make DNA when the rat is fed a meal with protein. A preparatory diet lacking in tryptophan is much less effective; a deficiency in any of the other indispensable compounds tested fails to prepare the liver for DNA synthesis. The results give hope that elucidation of the means by which methionine deprivation affects the nucleolus will also provide information on the regulation of nuclear DNA replication in liver. One attractive possibility is that the amino acid deficiency acts by producing some imbalance in protein metabolism.

Amino Acids↗
PubMed1976

The 7.1 S nuclear DNA polymerase and DNA replication in intact liver.

Just as after 70% hepatectomy, the activity of the 7.1 S DNA polymerase, but not the 3.2 S polymerase, is elevated in liver nuclei from unoperated animals in which hepatic DNA replication has been induced with a mixture of biochemicals or by a dietary manipulation. Again as with regenerating liver, the stimulated intact livers show a relationship between the increases in the enzyme activity and thymidine incorporation in vivo over a wide range of hepatic responses. These observations are consistent with a role for the 7.1 S activity in nuclear DNA replication. Cytosine arabinoside 5'-triphosphate and novobiocin can be used to distinguish between the 3.2 S and 7.1 S polymerases from nuclei of stimulated intact liver as well as of regenerating liver.

Animals↗
PubMed1975

Nucleolar changes in liver before the onset of deoxyribonucleic acid replication.

A mixture of chemicals was previously devised (3, 3', 5'-triiodo-L-thyronine, amino acids, a butyryl derivative of cyclic adenosine 3':5'-monophosphate, theophylline, and heparin) that induces nuclear DNA replication in the liver of the unoperated rat (Short, J., Tsukada, K., Rudert, W.A. 7 Lieberman, I. (1975) J. Biol. Chem. 250, 3602-3606). The stimulation of DNA synthesis with the complete solution is greater than the sum of the responses to the thyroid hormone alone and to a mixture of the remaining components of the inductive solution alone. The effects of the complete mixture and of parts of it on three parameters involving the hepatocyte nucleolus have now been examined in intact animals. The complete solution increases the level of RNA polymerase I (measured with isolated nuclei), the rate of ribosome synthesis, and the total volume of nucleoli per nucleus. Nucleolar hypertrophy is unique among the three changes in showing a requirement, just as for DNA synthesis, for all or almost all of the components of the complete mixture, including the thyroid hormone, for a maximal effect. Enlargement of nucleoli is detectable as early as 2 hours after the start of treatment with the complete mixture and a large proportion of the total hepatocyte population is involved. Hypertrophy is accompanied by an increase in nucleolar RNA content. N2-Monobutyryl cyclic guanosine 3':5'-monophosphate is not able to substitute for the cyclic adenine nucleotide.

Amino Acids↗
PubMed1975

Cyclic adenosine 3':5'-monophosphate and the induction of deoxyribonucleic acid synthesis in liver.

A mixture containing glucagon and thyroid hormone was previously devised that enhances markedly nuclear DNA replication and mitosis in the parenchymal liver cells of the unoperated rat. It is now shown that the glucagon of the stimulatory solution can be completely replaced by a mixture of a butyryl derivative of cyclic adenosine 3':5'-monophosphate and theophylline. Cyclic guanosine 3':5'-monophosphate and its butyryl derivatives and insulin and high levels of glucose are inactive. The inactivity of N2-monobutyryl cyclic guanosine 3':5'-monophosphate cannot be ascribed to rapid breakdown in the animal or to the impenetrability of the liver cell since the coumpound elevates the rate of hepatic amino acid transport and the activity of ornithine decarboxylase. The observation of others (MacManus, J.P., Franks, D.J., Youdale, T. & Braceland, B.M. (1972) Biochem. Biophys. Res. Commun. 49, 1201-1207) that the level of cylcic adenosine 3':5'-monophosphate is raised during most of the prereplicative period after 70% hepatectomy is confirmed. The evidence supports a positive role for adenosine 3':5-monophosphate in regulating DNA synthesis in the liver.

Aminoisobutyric Acids↗