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Results for “Pleiotropy”

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PubMed2005

Pleiotropy of tissue-specific growth factors: from neurons to vessels via the bone marrow.

Recent evidence has demonstrated that endothelial-specific growth factors affect the development of apparently unrelated organs and cells. Expanding this evidence further, new findings in this issue of the JCI show that neurotrophic factors can affect neovascularization. Neurotrophic factors achieve proangiogenic effects not only by directly affecting endothelial cells, but also by recruiting hematopoietic precursors. Further understanding of the biology of angiogenic factors, as well as of the function of hematopoietic cells in tissue neovascularization, will lead to improved therapeutic strategies for the treatment of diseases ranging from ischemia to cancer.

Animals↗
PubMed2004

Influence of dominance, leptokurtosis and pleiotropy of deleterious mutations on quantitative genetic variation at mutation-selection balance.

In models of maintenance of genetic variance (V (G)) it has often been assumed that mutant alleles act additively. However, experimental data show that the dominance coefficient varies among mutant alleles and those of large effect tend to be recessive. On the basis of empirical knowledge of mutations, a joint-effect model of pleiotropic and real stabilizing selection that includes dominance is constructed and analyzed. It is shown that dominance can dramatically alter the prediction of equilibrium V (G). Analysis indicates that for the situations where mutations are more recessive for fitness than for a quantitative trait, as supported by the available data, the joint-effect model predicts a significantly higher V (G) than does an additive model. Importantly, for what seem to be realistic distributions of mutational effects (i.e., many mutants may not affect the quantitative trait substantially but are likely to affect fitness), the observed high levels of genetic variation in the quantitative trait under strong apparent stabilizing selection can be generated. This investigation supports the hypothesis that most V (G) comes from the alleles nearly neutral for fitness in heterozygotes while apparent stabilizing selection is contributed mainly by the alleles of large effect on the quantitative trait. Thus considerations of dominance coefficients of mutations lend further support to our previous conclusion that mutation-selection balance is a plausible mechanism of the maintenance of the genetic variance in natural populations.

Genes, Dominant↗
PubMed2006

Statin-associated pleiotropy: possible beneficial effects beyond cholesterol reduction.

Because elevated serum cholesterol levels are strongly associated with coronary heart disease, cholesterol reduction by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (or statins) has been assumed to be the predominant, if not the only, mechanism underlying the beneficial effects of these drugs in cardiovascular diseases. Subgroup analyses of large clinical trials, however, have suggested that the beneficial effects of statins may extend to mechanisms beyond cholesterol reduction. Indeed, recent experimental and clinical evidence indicates that some of the cholesterol-independent or "pleiotropic" effects of statins may be mediated through improving or restoring endothelial function, enhancing the stability of atherosclerotic plaques, and decreasing oxidative stress and vascular inflammation.

Atherosclerosis↗
PubMed1996

Concepts of hemopoietic cell amplification. Synergy, redundancy and pleiotropy of cytokines affecting the regulation of erythropoiesis.

Hemopoietic cell amplification in vivo is regulated by various mechanisms which appear to be under control of many hemopoietic growth factors. Quiescent stem cells can be activated into cell cycle, dividing progenitor cells can reduce their cycle time, the differentiation velocity (i.e. transit-time) can be manipulated, apoptosis can be prevented, and finally, at least in the murine system, migration of cells between the microenvironments in marrow and spleen may take place. Perturbations of any of the parameters by which these mechanisms are defined, will affect in vivo blood cell production. In this review the consequences of these perturbations, and the role of growth factors herein, are discussed. These fundamental aspects of the regulation of hemopoiesis are illustrated with recent data showing the synergistic, redundant and pleiotropic effects of SCF, IL-11, EPO and G-CSF on the in vivo formation of erythrocytes. Given the overwhelming number of growth factor-related studies that are now appearing, a re-evaluation of data, available in the literature, in the context of the mechanistic approach of growth factor-dependent hemopoiesis which is presented in this paper, seems to be useful and warranted.

Animals↗
PubMed2005

The pleiotropy of telomerase against cell death.

The end of eukaryotic genomic DNA is capped by a specialized structure called as "telomere", which consists of the repetitive array of nucleotide sequence, TTAGGG, in humans and mice, and a variety of binding proteins. Telomerase is a ribonucleoprotein (RNP) complex responsible for the elongation of telomeres to maintain the genomic integrity, and is composed of telomerase reverse transcriptase (TERT), telomerase RNA component (TERC), and their associated factors regulating the catalytic activity of telomerase. Although it is now apparent that telomerase protects cells from apoptosis via the maintenance of genomic integrity by stabilizing telomeres, our understanding for the physiological role of telomerase is yet far from completion, and emerging evidence suggests that telomerase has additional extratelomeric roles in mediating cell survival and anti-apoptotic functions against various cytotoxic stresses. Here we summarize and discuss how telomerase and telomeres are involved in mediating cellular protection against apoptosis.

Animals↗
PubMed1991

Interleukin-2: counteracting pleiotropy by compartmentalization.

Interleukin-2 (IL-2) belongs to a series of mediators that are produced by T cells and exert multiple, pleiotropic effects in an autocrine or paracrine fashion. IL-2 plays a fundamental role in the ontogeny of developing T cells in the thymus and supports the growth or effector function of a wide array of immunologically relevant cells, including macrophages and B and NK lymphocytes, as well as a variety of different T-cell subpopulations. Nonetheless, the function of this lymphokine must be highly controlled in vivo to avoid systemic effects that might endanger the specificity of an immune response and result in autoimmune reactions. Accordingly, various mechanisms guarantee compartmentalization of IL-2, that is, chronological and spatial restriction of IL-2 production, bioavailability, and state of responsiveness. The secretion of IL-2, as well as the expression of the two components of the high-affinity IL-2 receptor (IL-2R), are developmentally controlled during ontogeny and, within the cellular immune system, are restricted to defined pre- and intrathymic stages of immature T cells or T-cell precursors. In the peripheral lymphoid organs, IL-2 is produced by a defined population of mature CD4+ T lymphocytes in which the IL-2 gene is transcribed or silenced, depending on the combination of antigenic and nonspecific activation signals to which the cell is exposed. Thus, the absence of certain costimulatory signals leads to a long-lasting inactivation of the IL-2 gene, a phenomenon that accompanies nondeletional T-cell tolerance. IL-2 has a short half-life and is secreted in apposition to the cell with which the T cell interacts. Expression of the high-affinity IL-2R is activation-dependent in most cell types. Thus, different mechanisms, intervening in all compartments relevant for the action of IL-2, together contribute to a restriction of IL-2 effects, conferring a relative specificity to this pleiotropic mediator.

Growth Substances↗
PubMed1990

The colony-stimulating factor 1 receptor: pleiotropy of signal-response coupling.

The colony-stimulating factor 1 receptor (CSF-1R) is a cell surface glycoprotein consisting of an extracellular ligand-binding domain, a single membrane-spanning segment, and an intracellular tyrosine kinase domain. Binding of CSF-1 activates the receptor kinase, leading to "autophosphorylation" of receptor subunits and the concomitant phosphorylation of a series of cellular proteins on tyrosine residues. The diverse effects of CSF-1 on mononuclear phagocyte proliferation, differentiation, survival, and macrophage effector function appear to reflect the ability of CSF-1R to simultaneously modulate the activities of a series of intracellular proteins that function in relaying biochemical signals. Sequences surrounding sites of ligand-induced tyrosine phosphorylation within CSF-1R may serve as targets for interactions with cellular effector proteins whose activities are modified by receptor binding, tyrosine phosphorylation, or both. The specificity of the cellular response to CSF-1 may depend, at least in part, on the differential coupling of the receptor to these "downstream" effectors in different cell types.

Animals↗
PubMed1986

Cutaneous malignant melanoma and familial dysplastic nevi: evidence for autosomal dominance and pleiotropy.

Segregation of familial cutaneous melanoma has been shown to be compatible with autosomal dominant transmission with incomplete penetrance. However, the combined phenotype of melanoma and a known melanoma-precursor lesion, the dysplastic nevus (DN), has not previously been found to fit a Mendelian model of inheritance using complex segregation analysis. Employing a life-table and disease-free survival analysis approach, we estimated the lifetime incidence of melanoma in the sibs and offspring of DN-affected individuals to be 46%, consistent with a highly penetrant, autosomal dominant mode of inheritance. To further elucidate the relationship between the two traits, we conducted a linkage analysis between the melanoma locus and a hypothetical DN locus, and obtained a maximum lod score of 3.857 at theta = .08. Furthermore, all families giving evidence for linkage were in the coupling phase and the maximum likelihood estimate of theta was not significantly different from 0 (P = .1). This provides evidence that the DN and melanoma traits may represent pleiotropic effects of a single, highly penetrant gene behaving in an autosomal dominant manner.

Disease Susceptibility↗
PubMed1998

Pleiotropy and the preservation of perfection

A mathematical model is presented in which a single mutation can affect multiple phenotypic characters, each of which is subject to stabilizing selection. A wide range of mutations is allowed, including ones that produce extremely small phenotypic changes. The analysis shows that, when three or more characters are affected by each mutation, a single optimal genetic sequence may become common. This result provides a hypothesis to explain the low levels of variation and low rates of substitution that are observed at some loci.

Journal Article↗
PubMed1998

Pleiotropy and the preservation of perfection.

A mathematical model is presented in which a single mutation can affect multiple phenotypic characters, each of which is subject to stabilizing selection. A wide range of mutations is allowed, including ones that produce extremely small phenotypic changes. The analysis shows that, when three or more characters are affected by each mutation, a single optimal genetic sequence may become common. This result provides a hypothesis to explain the low levels of variation and low rates of substitution that are observed at some loci.

Animals↗