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R L Hancock

Publications and source records attributed to R L Hancock.

At least 19 recordsLinked to original sources
PubMed1992

Theoretical mechanisms for synthesis of carcinogen-induced embryonic proteins: XXVII. Intermediate generalizations (Part B).

In this second section of generalizations, methylation, differentiation and carcinogenesis are reviewed. Special consideration is given to the alpha-fetoprotein gene which is used extensively as a model embryonic gene. Specific correlations are made between the glucocorticoid response element and the alpha-fetoprotein gene. A further correlation was made between retinoic acid and alpha-fetoprotein synthesis.

Animals↗
PubMed1992

Theoretical mechanisms for synthesis of carcinogen-induced embryonic proteins: XXVIII. Intermediate generalizations (Part C).

This is the final section of an intermediate phase of generalizations dealing with aspects of enhancers. It is concluded that a binding type protein(s) complex near a LTR segment. This creates destabilization of heterochromatin that allows transcription mechanisms. If this process is promoted by anomalous enhancer activity such as those produced by chemical inducers which modify chromatin states or cause hypomethylated enhancer regions, then normally repressed embryonic gene products, such as protooncogene growth factors, can be transcribed inappropriately to a specific developmental stage, eg post-embryonically.

Animals↗
PubMed1992

Derivation of a basic mechanism of control for embryonic genes as a specific subset.

The alpha-fetoprotein gene is conceived as being methylated in the zygote and according to the model is in a heterochromatic state and is therefore in a non-functional condition. Specific DNA methylase genes would produce methylases capable of alkylating enhancer regions of alpha-fetoprotein and certain proteins that would alter the heterochromatin condition. Also involved is a gene for the synthesis of a conformational-inducer protein that is proposed to be capable of blocking genic regions from reheterochromatizing. One of the pivotal events is the accumulation of S-adenosyl-L-methionine that reaches intracellular pool concentrations allowing other redundant active S-adenosyltransferase genes to become active. During embryogenesis specific conformational-inducer proteins would block genes such as the gene for albumin from reheterochromatizing while alpha-fetoprotein gene becomes heterochromatized during subsequent cell cycles. This heterochromatin is formed with embryonic type proteins sensitive to ribosylation-induced conformational changes. The increase in synthesis of alpha-fetoprotein followed by a decrease as albumin synthesis increases during embryogenesis is predicted by the scheme.

Animals↗
PubMed1992

Theoretical mechanisms for synthesis of carcinogen-induced embryonic proteins: XXVI. Evolutionary significance of carcinogen-induced embryonic gene activity.

Besides the major theme of this series of writings--that chemically derepressed embryonic genes are fundamental to the mechanisms of carcinogenesis, there appear to be other significant aspects to this process. Yeast cells have the ability to differentially respond to carcinogens and non-carcinogens by the activation of embryonic type genes that are also found in mammals. This strange relationship is interpreted here as being due to certain phylogetically conserved genes from yeasts existing also in mammals that are used in both organisms for the same process. For example, a protooncogene found in yeast cells or embryonic cells serves for rapid mitosis. Also yeast mating type genes have high homologies to homeotic domains and therefore may be prototype genes of homeotic genes, which are embryonic type genes in animals.

Biological Evolution↗
PubMed1992

Generalizing the control process for embryonic genes.

Embryonic genes are considered as a separate subset of genes with unique chromatin properties. There is a problem of defining the duration of perturbations of embryonic gene activity that has been chemically induced and the normal relatively longer lasting changes that occur during differentiation. This problem may be related to unique properties of the chromatin of embryonic genes. Methylation of DNA is thought to be only one level of control and the superstructure of chromatin involving heterochromatin is of equal importance to embryonic gene expression. Proto-oncogenes are considered to be embryonic type genes whose activities are regulated under the same mechanisms by which other embryonic genes are regulated. Control aspects are discussed in the light of i) repressor-derepressor and blocking-deblocking mechanisms, ii) activator genes, pseudogenes, LINES, SINES, v-type position effects, iii) effects of ethionine, and iv) steroid hormone effects especially with respect to a subset of repeated rRNA genes which are considered to be structured in embryonic type chromatin.

Animals↗
PubMed1992

Maintenance of embryonic gene activity into the adult state.

It is now apparent that certain embryonic gene activities may be maintained before the transition from embryonic to the adult state takes place. The consequence of such a condition could have far reaching results and create a totally new approach to biotechnology by dealing with epigenetic methods and not gene-splicing methods. For example, if a group of c-oncogenes, believed to be of the embryonic type (1) that are responsible for growth factors which regulate embryonic rates of growth, then large increases in growth rates during the adult stage should occur. Two major alterations seem to be required. One is the interference of DNA methylation patterns using such agents as ethionine (interfering with S-adenoysl-1-methionine synthesis) or azacytidine (interfering with DNA methylase activity). Secondly, a change in chromatin configuration (deheterochromatization?) with agents such as n-butyrate or hexamethylenebisacetamide (HMBA). Maintenance methylases would make the altered (hypomethylated) pattern of the perturbed chromatin invariant after the initial perturbation. Enhancer-promoter mechanics are probably pertinent to this process.

Animals↗
PubMed1991

Theoretical mechanisms for synthesis of carcinogen-induced embryonic proteins: intermediate generalizations.

A previous rendition of a mechanism for the induction of embryonic gene activity, derived from the viewpoint of agents capable of such inductions, concluded that a perturbed methylation pattern of DNA and/or chromatin proteins would be an essential feature. A more specific treatment of the mechanism centers on enhancer regions of proto-oncogenes as being the point of modification for any induction of new gene activity. DNA binding type proteins may be involved with deheterochromatization processes after complexing near long terminal repeat segments containing enhancer elements. Chemical carcinogens and steroids would modify the chromatin and directly or indirectly interfere with maintenance DNA methylation. The resulting hypomethylated enhancer and promoter regions would allow for enhancer mechanisms to activate repressed embryonic genes inappropriate to the developmental stage forcing embryonic features to be expressed by differentiating (or differentiated) cells.

Animals↗
PubMed1991

Theoretical mechanisms for synthesis of carcinogen-induced embryonic proteins: XXIV. Repeated embryonic genes in liver.

Many embryonic genes may be sets of repeated genes. Processes of differentiation where the quantity of gene activity changes during embryogenesis may not reflect the transcription rate per se but instead be a result of the state of expression of constitutive repeated genes. Such repeated genes (in fact or theory) is dealt with here for embryonic, adult and neoplastic liver. Explanations are presented for 1) the variation in ATP: L-methionine S-adenosyltransferase activity in spontaneous hepatomas and embryonic liver; 2) differences tRNA L-methionine S-adenosyltransferase activity in spontaneous hepatomas and embryonic liver; 3) differences in tRNA methylase activity in embryonic liver, hepatomas of varying levels of differentiation, and ethionine treated liver; 4) relationships between rRNA genes and nucleolar organizers; and 5) the possibilities involving c-onc genes (proto-oncogenes) for situations of 'over-expression' in neoplastic and embryonic liver.

Animals↗
PubMed1991

Hereditary and environmental influences on blood pressure values of premenopausal women and their college-age daughters.

Blood pressure (BP) and environmental (dietary/lifestyle) variables were measured in 62 healthy normotensive pairs of premenopausal mothers (44.3 years) and their college-age consanguineous daughters (18.7 years) to estimate the relative contributions of genetic vs environmental factors on BP. As expected, the mothers had significantly higher systolic (SBP) and diastolic (DBP) blood pressures than the daughters (p less than 0.004 and 0.012, respectively). Among the dietary/lifestyle variables measured, mothers were found to have significantly higher mean weight and body mass index (BMI) (p less than 0.009 and 0.001, respectively), and significantly lower lean body mass (LBM) and calcium intake than their daughters (p less than 0.003 and 0.037, respectively). Significant correlations were found between mean BP of the mothers and their mean weight and BMI. No significant correlations existed for the daughters. The familial resemblances between BP of the mothers and daughters were relatively low, i.e., 0.14 for SBP and 0.19 for DBP. From these findings we conclude that the higher BP values with increased age among this healthy female population primarily result from an increase in BMI and a shift from lean to fat mass, as measured by midarm circumference. Our results suggest that environmental factors, i.e., excessive energy intake over time, accompanied by decreased physical activity, are primarily responsible for the greater indices of body fat and the higher BPs observed in this sample of healthy premenopausal women.

Adipose Tissue↗
PubMed1989

Familial resemblance of radial bone mass between premenopausal mothers and their college-age daughters.

The influences of heredity and environmental factors on radial bone mass were evaluated in 84 premenopausal mothers with their biological daughters (ages 18-22). Mid- and distal radial bone mineral content (BMC) and density (BMD) were assessed using single-photon absorptiometry. As a group, the daughters (mean age 18.6 years) had 5-10% less bone mass at both the distal and midradial sites than their mothers (mean age 44.2 years). Familial resemblance estimates showed significant relationships between mothers and daughters for mid- and distal BMC and BMD after considering the influence of body mass index (BMI). Daughters with a maternal family history of osteoporosis had 6-7% lower but nonsignificant values of mid- (P = 0.086) and distal BMC (P = 0.075) compared to values of women with a negative family history, whereas mothers with a positive family history had 3-4% lower (NS) values of distal and mid-BMC compared to those of mothers with a negative family history after adjustment for BMI. Multiple regression analyses showed BMI to be the most important determinant of the bone values of the mothers, and both BMI and dietary calcium intake were found to be significant for the daughters. The findings of this study suggest that hereditary contributions from the mothers play an overwhelmingly critical role in the accrual of bone mass by their daughters by ages 18-22, but that environmental influences on bone consolidation during the premenopausal decades may be more important in promoting optimal (peak) bone mass and thereby may help to delay the postmenopausal onset of osteoporotic fractures.

Adolescent↗
PubMed1989

Theoretical mechanisms for synthesis of carcinogen-induced embryonic proteins: XXIII. Enhancer theory.

Embryonic gene enhancers may be controlled by deheterochromatization of genes of trans-acting factors caused by altered methylation states of hypersensitive chromatin. Such specific chromatin sites would have a certain required helical pitch (X-type DNA). Non-core regions surrounding the enhancer motif would allow interactions with specific cell type promoters. Differences in embryonic and adult type genes may be reduced to these enhancer activities and certain trans-acting proteins effecting these genic control elements. Furthermore all spurious embryonic gene activities of neoplasms may also be due to such factors. Even pleotrophic and cascade phenomena in dysdifferentiation processes may be described in terms of enhancer mechanisms. Duplications of enhancer sequences may be fundamental to the potential of hyperactivity by embryonic type genes. Examples of this would be alpha-fetoprotein correlations with enhancer activity and possibly increased nucleolar organizer activity of embryonic cells. The manner by which chemical carcinogens would be involved with enhancer processes would be via "key" mechanisms that have been presented previously.

Embryo, Mammalian↗
PubMed1988

Theoretical mechanisms for synthesis of carcinogen-induced embryonic proteins: XIX. Embryonic genes.

The methylation status of a conformation-inducer protein that would effect the status of DNA in relation to its ability to be in an active or inactive state is proposed to be central in the regulation of embryonic genes. Thus a distinction can be drawn between induceable "adult" genes such as glucocorticoid induced tyrosine aminotransferase and induceable "embryonic" genes such as ethionine induced alpha-fetoprotein. However, in the proposed mechanism the methylation of DNA is also important in that a hypomethylated state of a CCGG sequence of a promotor region for a conformation-induced protein gene is required to initiate the induction events.

Animals↗
PubMed1987

Theoretical mechanisms for synthesis of carcinogen-induced embryonic proteins: XVII. Heterochromatin mechanisms.

A mechanism for induced embryonic gene expression via a process of deheterochromatization using a model carcinogen has been derived. First ethionine becomes activated to S-adenosyl-L-ethionine which inhibits the methylation of nicotinamide, a resulting product of polyADP-ribose polymerase. This causes hyporibosylated nucleosome core histones which normally would base pair by virtue of the adenine moieties with thymidine-rich regions of DNA, being the precursor of heterochromatin. Thus in the anomalous state a deheterochromatized condition of embryonic genes would be created. Possibly embryonic genes are dispersed in AT-rich regions potentially capable of becoming hyperspiralized by this process. Repressable embryonic genes would not be inactivated. It was also noted that hyomethylated non-histone chromatin proteins cause an extension of the nucleosome chanins which would also favor the above situation. This mechanism explains our experimental findings of the relatively rapid reversal of ethionine induced alpha-fetoprotein levels by methionine. The process of heterochromatization is hypothesized to be induced by short (pentanucleotides) moities of poly (ADP-ribose), formed on core histones, that hydrogen bond to thymidine rich inter Nu body DNA.

Animals↗
PubMed1985

Theoretical mechanisms for synthesis of carcinogen-induced embryonic proteins: XIII. Mutational and non-mutational mechanisms as subsets of a more general mechanism. Part B--hereditary tyrosinemia.

In this mini-series three different examples of the etiology for the induction of alpha-fetoprotein and hepatocarcinogenesis have been chosen. The first paper describes the mechanism using the non-mutagen, ethionine. In this paper the mechanism is derived by virtue of a mutation that causes a deficiency in fumarylacetoacetate fumarylhydrolase activity with subsequent accumulation of fumarylacetoacetate that is an inhibitor of ATP: L-methionine S-adenosyltransferase. It is hypothesized that the chronically low levels of active methyl groups disallows base-pairing by the adenine moiety of S-adenosyl-L-methionine and the repressed conformation of the alpha-fetoprotein gene is altered and subsequent transcription takes place. The same or similar process occurs with the subset of genes (embryonically repressed) that as a special group of active genes gives embryonic features to a quasi-differentiated stem cell causing "dysdifferentiation" to a neoplastic state.

Amino Acid Metabolism, Inborn Errors↗
PubMed1979

Theoretical mechanisms for synthesis of carcinogen-induced embryonic proteins: IV. The viruses.

Speculations are developed for a mechanism by which oncogenic viruses can induce alterations in cells allowing them to express embryonic genes. It is suggested that if viral deoxyribonucleic acid, directly or via ribonucleic acid directed deoxyribonucleic acid polymerase activity becomes inserted at particular euchromatin - heterochromatin junctions of quasidifferentiated stem-like cells, then deheterochromatization may result, causing in turn derepression of genes for acidic protein phosphokinases. This sets into motion a series of events including altered acid protein repressors of embryonic genes which are repressed by uniquely weak type repressors. This explains how viruses can act as specific embryonic gene-inducing agents similar to chemical inducing agents such as the hepatocarcinogen ethinine.

Adult↗
PubMed1979

Theoretical mechanisms for synthesis of carcinogen-induced embryonic proteins. V. The steroids.

Since the induction of neoplastic cells by steroids has been well documented, an attempt is made to formulate a mechanism for explaining the resultant embryonic features of such tumour cells. Special emphasis is given to estrogen receptor complexes and their effect on chromatin proteins. Specifically a mechanism is presented for estradiol-17-beta and its ability to alter the gene expression (derepression) of mammary gland epithelial cells. In this model we explore the possible effects of small differences in receptor or repressor proteins associated with estrogens to translate quantitative steroid administration into qualitative cellular responses.

Animals↗