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E Zuckerkandl

Publications and source records attributed to E Zuckerkandl.

At least 37 records · Page 2Linked to original sources
PubMed1988

Concentration-affinity equivalence in gene regulation: convergence of genetic and environmental effects.

It is proposed that equivalent phenotypic effects can be obtained by either structural changes in macromolecules involved in gene regulation or changes in activity of the structurally unaltered macromolecules. This equivalence between changes in activity (concentration) and changes in structure can come into play within physiologically plausible limits and seems to represent an important interface between environment and genome--namely, between environmentally determined and genetically determined gene expression. The equivalence principle helps explain the appearance of phenocopies. It also points to a general pathway favorable to the occurrence, during evolution, of frequent episodes corresponding to Waddington's genetic assimilation and is likely to represent one component of the system responsible for the high frequency of recurrence of parallel evolution.

Biological Evolution↗
PubMed1988

Down-regulation of an abundant cellular protein associated with tumor progression.

Alteration of gene expression in neoplastic cells can be detected by two-dimensional gel electrophoresis. This study reports the altered synthesis of an abundant cellular protein, p29, accompanying tumorigenic transformation of immortalized fibroblasts induced by transfection with oncogenic DNA. Cell lines derived from morphologically transformed foci synthesized p29 at 60-75% reduced levels compared with untransformed parental cells. Upon inoculation into syngeneic immunocompetent animals, transformed cells gave rise to tumors which were excised and established in culture. The amount of p29 in both focal and tumor-derived lines was inversely correlated with the latent period for tumor formation. In cell lines with a tumor latency of 12-20 days, the level of p29 was decreased by 90-99%. In rapidly tumorigenic cells with a short latency (3-6 days), p29 synthesis was not detectable. These data demonstrate that p29 may be a sensitive and reliable marker for tumor progression of fibroblasts.

Animals↗
PubMed1987

On the molecular evolutionary clock.

The conceptual framework surrounding the origin of the molecular evolutionary clock and circumstances of this origin are described. In regard to the quest for the best available molecular clocks, a return to protein clocks is conditionally recommended. On the basis of recent data and certain considerations, it is pointed out that the realm of neutrality in evolution is probably less extensive than is now commonly thought, in the three distinct senses of the term neutrality--neutrality as nonfunctionality of mutations, neutrality as equifunctionality of mutations, and neutrality as a mode of fixation of mutations. The possibility is raised that complex sets of interacting components forming a system that is bounded with respect to its environment may quite generally display an intrinsic trend to a quasi-clockwise evolutionary behavior.

Biological Evolution↗
PubMed1986

Quantitative protein profiling: determining lexotypes.

The lexotype of a cell is defined as a set of quantitative characters of its informational macromolecular gene products, notably proteins, as observed under specified environmental conditions. This definition can be applied to cells in several ways that need to be distinguished. It can refer to the protein lexotype, to RNA lexotypes; to the steady-state lexotype, synthesis lexotype, functional protein lexotype; to the in situ lexotype and standard-environment lexotype. When used without qualification, the term lexotype may be applied to the standard-environment, steady-state protein lexotype. Some difficulties that currently limit our ability to determine lexotypes are assessed. Reasons are given why abnormal cellular states, such as states of disease, should often be characterizable by means of protein markers not themselves involved in the disease process and why one expects to find markers in tissues other than the one in which a certain pathological process may be anticipated to occur. There are three routes through which biological systems can produce secondary protein markers, namely through gene regulatory chains, through chromosomal gene linkage, and through "physiological linkage" of genes. The partly stable, partly shifting, yet defined relations between tissue lexotypes are considered. A number of potentially important fields of application of rigorous quantitative analyses of protein profiles are listed. One particular use of the technology is to investigate a hypothesis linking aging to degenerative diseases with late onset. According to this hypothesis, such diseases appear in later life as the cellular concentration of the active form of a protein passes a certain threshold in the course of the aging process.

Aging↗
PubMed1986

Age-dependent changes in proteins of Drosophila melanogaster.

Several molecular theories of aging postulate that there are age-dependent changes in gene expression and that these changes contribute to the reduction in the viability of senescent cells. High-resolution, semiautomated, quantitative two-dimensional gel electrophoresis of many soluble proteins was used to test this hypothesis in Drosophila. Two-dimensional protein gel patterns were analyzed for each of three age groups of [(35)S]methionine-labeled adult male Drosophila melanogaster, which, except for their spermatocytes, consist entirely of fixed postmitotic cells. Seven relatively abundant polypeptides expressed in middle-aged (28-day-old) flies were absent in both young(10-day-old) and old (44-day-old) flies. Quantitative analyses of an additional 100 polypeptides were carried out by computer-assisted microdensitometry of fluorograms of the gel preparations. These analyses revealed a significant age-related heterogeneity in the quantitative distribution of radiolabel in these proteins. The data indicate that the qualitative pattern of gene expression is identical in young and old flies, but that profound quantitative changes occur in the expression of proteins during the Drosophila life-span.

Aging↗
PubMed1986

Polite DNA: functional density and functional compatibility in genomes.

Certain as yet poorly defined functions of DNA appear to involve collectively domain-sized sequences. It is proposed that most sequence segments within a domain may be either functionally superfluous or instrumental, depending on how many related sequences are present in the domain. When redundant and functionally dispensable, such DNA segments presumably still have to conform to compositional or sequence-motif patterns that characterize the domain. In its relations with neighboring sequences, such DNA is required to be "polite." Polite DNA is DNA that, without being crucially involved in function, is subject to constraints of conformity and, through its base composition, respects a function for which it is not required. This concept is developed by contrasting the distribution of specific and general functions over DNA with this distribution as found in proteins and by distinguishing functional compatibility from pivotal functionality. The sequence constraints to which heterochromatin as well as, apparently, long interspersed repetitive sequences are known to be subject seem to imply that DNA, even when it does not carry out a pivotal function, is indeed, at the very least, required to be polite.

Animals↗
PubMed1982

Effects of intake of L-ascorbic acid on the incidence of dermal neoplasms induced in mice by ultraviolet light.

We have carried out a study of large malignant skin tumors (squamous cell carcinomas) and other lesions in hairless mice (groups of 38-45) intermittently exposed to ultraviolet light over a period of 15 weeks, beginning when the mice were about 10 weeks old. The several groups were given a standard diet with 0%, 0.3%, 5%, and 10% added L-ascorbic acid (vitamin C) throughout the study. No lesions developed in unirradiated control groups. The lesions were counted every 14 days for 4 months, beginning 4 weeks before the end of the period of irradiation. The observed incidence of lesions of several sizes during successive time periods was analyzed by the statistical method recommended by a committee of the International Agency for Research on Cancer. A pronounced effect of vitamin C in decreasing the incidence and delaying the onset of the malignant lesions was observed with high statistical significance.

Animals↗
PubMed1981

A general function of noncoding polynucleotide sequences. Mass binding of transconformational proteins.

It is proposed that a general function of noncoding DNA and RNA sequences in higher organisms (intergenic and intervening sequences) is to provide multiple binding sites over long stretches of polynucleotide for certain types of regulatory proteins. Through the building up or abolishing of high-order structures, these proteins either sequester sites for the control of, e.g., transcription or make the sites available to local molecular signals. If this is to take place, the existence of a 'c-value paradox' becomes a requirement. Multiple binding sites for a given protein may recur in the form of a sequence 'motif' that is variable within certain limits. Noncoding sequences of the chickens ovalbumin gene furnish an appropriate example of a sequence motif. GAAAATT. Its improbably high frequency and significant periodicity are both absent from the coding sequences of the same gene and from the noncoding sequences of a differently controlled gene in the same organisms, the preproinsulin gene. This distribution of a sequence motif is in keeping with the concepts outlined. Low specificity of sequences that bind protein is likely to be compatible with highly specific conformational changes.

Animals↗
PubMed1976

Gene control in eukaryotes and the c-value paradox "excess" DNA as an impediment to transcription of coding sequences.

Ways in which control of gene activity may lead to the observed high DNA content per haploid eukaryote genome are examined. It is proposed that deoxyribonucleoprotein (DNP) acts as a barrier to transcription at two distinct structural levels. At the lower level, melting of the nucleosome supercoil (quaternary structure) and of the nucleosomes (tertiary structure) might be brought about by the process of transcription itself. After unwinding the barrier section, the polymerase would eventually reach the structural gene. The transcripts of noncoding sequences, at least as far as their "unique" sequence components are concerned, may thus have filled their main function through the very process of transcription. The possibility of an inverse relationship between the length of the DNP barrier and the rates of transcription of the coding sequences is to some extent supported by available data. Different modes of coordination between the transcription of mRNA and of hnRNA from a single functional unit of gene action (funga) are considered. An analysis of gene control at high structural levels of DNP is made on the basis of other data, in relation to the concepts of eurygenic and stenogenic control. The concept of a euryon is introduced, namely of a set of linked fugas under common eurygenic control. Structure of order higher than quaternary can be inferred to exist in larger chromomeres of polytene chromosomes and in corresponding sections of ordinary chromosomes. Only moderate amounts of highest order interphase euchromatic structure are likely to be able to be accomodated in average chromomeres and none in very thin chromomeres. Puffs are interpreted as the melting of highest order interphase structure, and the absence of puffs during transcription as the absence of this highest order structure in the resting state of the chromomeres. Genes that are constantly active in all tissues may dispense with highest order interphase structure and with the corresponding control mechanism, and the fugas involved thus may not puff. Puffs, large chromomeres and highest order interphase euchromatic DNP structure seem to be correlated with genes that need to be transcribed only under certain developmental conditions. It is proposed that the function of high order structure is to sequester genetic material, namely mainly controller sequences. Since such high order structure, in most cases, would be built up to house the controller dependencies of just one structural gene, the amount of DNA per structural gene needed for gene control would be considerable, and the concept, if correct, would go a long way towards explaining the c-value paradox ("excess" DNA in eukaryotes). In eurygenic determination, the high order structure is thought to be conditioned for melting or to actually melt to an intermediate level of structure. From there, stenogenic control, leading to transcription, is considered to carry the melting process further to yet lower structural levels...

Animals↗
PubMed1976

Evolutionary processes and evolutionary noise at the molecular level. II. A selectionist model for random fixations in proteins.

On account, notably, of a competition between different component functions for individual sites in polypeptide chains, each protein molecule represents a functional compromise, with some functions optimized, but the overall state of the molecule "suboptimal". The proposal is made that the selection coefficient relating to a protein molecule under given conditions can in principle be broken down into partial selection coefficients relevant to the different functions that the molecule carries out. At general-function sites, each fixation improves some function, while others deteriorate, at first nonsignificantly, and the overall adaptive state of the molecule fluctuates around its maximum. A selective mechanism is described whereby kaleidoscopic changes in primary structure at variable sites are indefinitely promoted, independently of any environmental changes and with the molecule remaining close to a state of maximal overall adaptation. The paradoxical aspect of this proposal is analyzed. The implication of specific functions in substitutions at general-function sites is noted. Further, it is shown that a certain category of changes in the internal environment of the organism can be integrated into the constant-environmental model for selection. Genetic sufficiency is considered a notion more adequate than genetic optimality for describing biological fitness and for providing a basis for the present model. On this basis selection occurs without genetic load. Multipolymorphism is one of the consequences. Several lines of evidence, in particular observations on polymorphism in deep sea organisms, seem to support the model. It is pointed out that it provides a theoretical foundation for a molecular evolutionary clock. The theoretical constancy of the clock depends on the constancy of functional density. The question of the evolution of functional density is examined. Comparisons of observed substitution frequencies with values expected on a random basis are rejected as a measure of the contribution to evolution of nondetermination. They are considered to reflect a hierarchy in the resistance of the molecules to different amino acid residues as substituents. A limited component of "true" randomness, again accompanied by selection, is on the other hand provided by the model. Most amino acid substitutions are considered evolutionary noise, even though noise compatible with selection. It is proposed that evolutionary significant substitutions may be identified by monitoring changes in functional density and weighted functional density.

Alleles↗
PubMed1976

Evolutionary processes and evolutionary noise at the molecular level. I. Functional density in proteins.

The distinction between molecular sites that mainly carry out general functions and sites committed to specific functions is analyzed, notably in terms of different evolutionary variabilities. Functional density is defined as the proportion of sites involved in specific functions. Weighted functional density, by representing the relative variability at specific-function sites is to some extent a measure of the specificity of molecular interactions. The relationship between general- and specific-function sites on the one hand the covarions of Fitch on the other is discussed. The functional "degeneracy" of amino acids is described as increasing the interdependence of general functions. It is predicted that proteins tht do not possess general-function sites besides their specific-function sites tend to "freeze" their primary structure, according to an evolutionary process that is an autocatalytic function of the decrease in site variability. This limits the use of weighted functional density as an indicator of the overall degree of interaction specificity of a protein to values that are not close to unity.

Amino Acid Sequence↗
PubMed1976

Detection of a diffusible factor controlling the synthesis of a single hemoglobin chain in mice.

The synthesis of hemoglobin alpha-chains was investigated in splenic colonies derived from syngenic colony-forming units injected in lethally irradiated C3H mice. Whereas normal adult mice of this strain synthesize two structurally distinct alpha-chains, the "alphaC57" and the "alpha NB", chains, it was found that erythrocytes from splenic colonies of irradiated recipient mice contained no alpha chain of the C57 type. Daily injection of serum from adult C3H mice into irradiated recipient mice of the same strain stimulates the synthesis of alphaC57 chain, whereas the injection of serum of lethally irradiated mice, drawn 8 days after irradiation, does not. It is concluded that the serum of adult C3H mice contains one or several factors that are responsible for the differential activation of the synthesis of the alphaC57 globin chain. This factor is shown to be associated exclusively with a high molecular weight fraction of serum.

Animals↗
PubMed1975

The appearance of new structures and functions in proteins during evolution.

The likelihood of a de novo generation of classes of efficient proteins through neoformation of DNA, through modification of expressed DNA, and through modification of nonexpressed DNA is examined. So is the likelihood that newly formed inefficient enzymes be turned into efficient enzymes. The conclusions are that neither gene duplicates nor dormant genes represent promising materials for a de novo generation of protein classes, that (with exceptions) such generation is unlikely to have taken place in recent evolution, that new structural genes must nearly consistently derive from preexisting structural genes, and that new functions can be evolved only on the basis of old proteins. Conditions of protein evolution in prokaryotes suggest that the saltatory formation of protein classes is as unlikely in prokaryotes as in eukaryotes. Data on the history of a few protein classes are reviewed to illustrate the preceding inferences. The analysis leads to the hypothesis that most protein classes originated before the major elements of the translation apparatus of modern cells were fully evolved. If simple sequence DNA is turned into structural genes by evolution, this process (again with exceptions) is considered to have taken place only at that very remote period. A polyphyletic origin of proteins is thought to date back to the same era. It is proposed that the development of genic multiplicity and of marked structural and functional diversity of proteins may have come about in the earliest cells primarily through the independent generation of structurally different polymerases in different protocells, followed by cell conjugation and the subsequent use by enriched cells of supernumerary types of polymerase for evolving further functions. Functional growth, as it took place at early times, is briefly discussed as well as functional change. The foundations for new functional developments in old proteins are analyzed. In considering the evolutionary recovery of lost functions, aspects of cell differentiation and gene regulation are linked with the evolutionary picture. The distinction between eurygenic and stemogenic control of gene activity is used. Next to gene deletion, cell and tissue deletion is held to be an event of general evolutionary significance, through cell and tissue origination that presumably accompanies the restoration of a lost molecular function.

Amino Acids↗
PubMed1975

The in vitro cellular synthesis of hemoglobin components in various media and its relevance to the concept of stenogenic and eurygenic states of differentiation.

The increase above normal in the rate of synthesis of human fetal hemoglobin in incubated cells from adults, as observed previously, is only relative. The addition of serum to the incubation medium tends to reestablish the normal ratio of rates. In the absence of serum the decrease in rates of synthesis affects most strongly the hemoglobin component, whichever it be, that is synthesized more intensively at the cell stage under consideration. This is brought out by the comparison of the effects of different media on fetal and adult cells. The data lead to the definition of the concept of stenogenic and eurygenic states of differentiation.

Bone Marrow↗