Theoretical mechanisms for synthesis of carcinogen-induced embryonic proteins: VII genic mechanisms

Abstract

The expression of embryonic phenotypic entities induced by a variety of carcinogenic agents can be unified by proposing a process of deheterochromatization. This central process can occur from purely genetic recombinations through the phenomenon of “position effect” of certain new gene proximities near facultative heterochromatin. The same effect may occur through genetic recombinations of Mendelian traits exemplified by the induction of melanomas in platy-swordtail hybrids or by specific chromosomal alterations through mechanisms of translocations, etc. as seen in human leukemias. It is further proposed that some of these chromosomal alterations involve the “turning on” of sarc-like genes i.e. protein phosphokinases which in turn cause alterations in the chromatin construct of further heterochromatic areas thus leading to a cascade phenomenon as discussed previously. (1). Viral processes also would be categorized in this latter mode since they would introduce aberrant protein phosphokinase genes into the cell. An entirely different origin of dehetero-chromatization would be achieved by such agents as ethionine. Ethionine is known to react with adenosine triphosphate to produce S-adenosyl-ethionine. This compound interferes with normal methylation reactions and produces hypomethylated transfer ribonucleic acid and deoxyribonucleic acid. Hypomethylated deoxyribonucleic acid has been correlated with the activation of globin genes. The mechanism may include the same deheterochromatization process although the choice between hypomethylated proteins which may also exist in these states or hypomethylated deoxyribonucleic acid as being basic to this mechanism, cannot be made. This hypothesis will explain how heredity can be a factor similar to other carcinogenic events. Furthermore it may explain processes such as the synergism between viruses and carcinogens. This unified theory would predict that the position effect may cause carcinogenic events only if the protein phosphokinase gene is involved. It would also require that protein phosphokinase genes are redundant and occur near or at the specific chromosomal anomalies described thus far. Minor isologous transfer ribonucleic acids are probably the result of modifications of minor nucleotides and, at least for the methylated subset of these, amy involve embryonic genes (2). This process appears to present transcriptional control mechanisms with an anomaly such that the overall phenotype of the embryo becomes expressed which includes further (embryonic) features of control. Other chemicals may modify heterochromatin by intercalation causing a “pseudo-position effect” or chemicals such as the drug phenobarbital, a tumor promotor, may induce certain enzymic changes, such as protein methylation or hydroxylations that result in the same chromatin alterations alluded to previously. Still other chemicals, the mutagenic and alkylating agents, could cause alterations similar to those induced by anomalous enzymic bioalkylations. Steroids as carcinogens have already been described in terms of “groove distorters” (3). Such a process fits well with a process of deheterochromatization. Deoxyribonucleic acid alterations such as those that would occur during groove distortion should result in hierarchical structural chromatin changes. However, the theory does not predict several features of carcinogenesis such as latency and certain requirements of chronic administration of carcinogenic agents.