Control Of Animal Cell Proliferation Research Articles

HumanE2F5 gene is oncogenic in primary rodent cells and is amplified in human breast tumors

E2F transcription factors (E2F1 to 6) are central players in the control of animal cell proliferation as regulators of genes involved in cell cycle progression and in transformation. In this report, we have investigated the potential involvement of the E2F5 gene in tumorigenesis. We show that E2F5 can promote the formation of morphologically transformed foci in primary baby rat kidney cells (BRK) when it is overexpressed in the presence of its heterodimeric partner DP1 and activated RAS. This suggests that E2F5 behaves like a MYC-type cooperating oncogene in functional assays, prompting us to monitor potential amplifications of the E2F5 gene in primary human tumors. We mapped the human E2F5 gene to 8q21.1-21.3 equidistant from the MOS (8q12) and MYC (8q24) oncogenes. Since the long arm of chromosome 8 is frequently the site of increased gene copy number (ICN) in breast cancer, we screened 442 breast tumor DNAs for gains of E2F5, MOS, and MYC genes. The three genes showed ICN, albeit at variable incidence and levels of amplification, with the ICN of E2F5 occurring concomitantly with those of MOS and/or MYC in almost half of the cases. Moreover, a marked increase of the 2. 5-kb E2F5 transcript was also detected in some tumors and tumor cell lines. In conclusion, the evidence that sustained unregulated expression of E2F5 can cooperate with other oncogenes to promote cell transformation in functional assays, together with the detection of chromosomal amplifications and overexpressions of the E2F5 gene in breast tumors, provides the first indications that E2F5 deregulation may have a role in human tumor development.

Cytokinin metabolism: implications for regulation of plant growth and development

This review describes recent advances in the study of cytokinin metabolism. It highlights how plant development is influenced by cytokinin synthesis, conjugation and conjugate hydrolysis, and what has been learned of the enzymes that regulate these processes. Although cytokinin metabolism and physiology are complex issues, some of the key enzymatic players are now being identified. This holds out the prospect of rapid progress in the near future. Just as much of what we know about the control of animal cell proliferation was learned by studying the cellular counterparts of viral oncogenes, so important information about the control of plant development by phytohormones has come from studying the genes of bacterial pathogens that subvert host phytohormone metabolism to their own advantage. We will focus on what has been learned from the use of such genes, and describe progress in identifying their functional counterparts in plants.

Interleukin‐6 production by the blast cells of acute myeloblastic leukemia: Regulation by endogenous interleukin‐1 and biological implications

Coordinate production of interleukin-1 beta (IL-1 beta) and granulocyte macrophage-colony stimulating factor (GM-CSF) or IL-6 by the blast cells of acute myeloblastic leukemia (AML) and normal peripheral blood leukocytes have been previously reported (van der Shoot et al.: Blood 74:2081-2087, 1989; Bradbury et al.: Leukemia 4:44-47 1990a, British Journal of Haematology 16:(in press), 1990b; Rodriguez-Cimadevilla et al.: Blood 76:1481-1489, 1990; Schindler et al.: Blood 75:40-47, 1990). In the present study, we show that IL-6 production by AML blasts is up-regulated by endogenously produced IL-1 beta. Neutralization of the endogenous source of IL-1 results in a significant decrease in IL-6 production, as determined by ELISA. Conversely, exposure of AML blasts to IL-1 alpha results in a significant increase in IL-6 production in 10 of 16 patient samples. Antibodies against IL-1 alpha and -beta also cause a drastic decrease in IL-6 and GM-CSF gene expression by the cells, suggesting that cytokine gene expression in AML blasts is driven, at least in part, by endogenous IL-1. The biologic significance of IL-6 production in culture of AML blasts has been addressed using a neutralizing antibody against IL-6. Our data indicate that IL-6 is important for the survival of clonogenic blasts in culture. In contrast, the survival of the total population of blasts is IL-6-independent, as assessed by the integrity of cellular DNA, even in the presence of anti-IL-6. These observations are consistent with the view that AML blasts might be organized as a lineage, with comparable hierarchy as in normal hemopoiesis and, perhaps, increased heterogeneity despite a homogenous appearance (McCulloch and Till: Blood Cells 7:63-77, 1981; Buick and McCulloch: Control of Animal Cell Proliferation. Academic Press, New York, vol. 1, pp. 25-57, 1985). Buick and McCulloch have identified a subpopulation of AML clonogenic cells with stem-cell-like properties, and suggested that the majority of blasts may have undergone a determination-like step. Our data indicate a marked difference in IL-6 requirement for cell survival between precursors and the majority of blasts, suggesting that IL-6 responsiveness may decrease following a determination-like event, i.e., the reduction in proliferative capacity.

Polypeptide growth factors in uterine tissues and secretions.

It has often been speculated that uterine secretions (histotrophe) are involved in regulating the attachment, implantation, nutrition and growth of the conceptus (Corner, 1921; Amoroso, 1952; Roberts & Bazer, 1988; Biggers, 1988). However, the factors responsible and the mechanisms involved have not been clearly defined. Work over the past decade has firmly established the involvement of peptide and polypeptide growth factors in the control of animal cell proliferation (see Evered et al., 1985). These results raise the intriguing possibility that uterus-derived growth factors may play a role in regulating the growth of the conceptus. This could occur via a paracrine pathway involving the secretion into the uterine lumen of factors which, on binding to specific cellular receptors, would directly stimulate DNA synthesis and division in cells of the developing conceptus. Alternatively, the factors could affect aspects of uterine cell proliferation (e.g. angiogenesis and vascularization) which may be important for conceptus attachment, implantation or nutrition. Recent evidence indicates that polypeptide growth factors are indeed present in the uterus and its secretions. Several such factors have been identified and, at least in some cases, synthesis of the factor appears to be regulated by steroid hormones (Table 1).

Book Review: Control of Animal Cell Proliferation

Book Review: Control of Animal Cell Proliferation

Control of animal cell proliferation.

Present understanding of the control of animal cell proliferation is summarized briefly. Major gaps in present knowledge are listed. Models of growth control are discussed.

Nutrient uptake and control of animal cell proliferation

AbstractThe division of fibroblast‐like cells in culture can be regulated by cell density, serum, and various growth factors. This system has been widely utilized as a model to study the regulation of cell proliferation. There are many physiological and metabolic changes that correlate with the proliferative state of the cell. These include changes in morphology, cyclic nucleotide levels, enzyme activities, and certain cell surface properties such as nutrient uptake and chemical composition of the plasma membrane. Of primary concern is determination of which changes might be critical links in the control of cell proliferation and which ones are simply correlated but not causally involved with cell growth. We have discussed evidence which has strongly suggested a fundamental role for uptake of certain nutrients in the regulation of cell growth. In addition, we have presented several methods allowing a critical analysis of a putative cause and effect relationship between nutrient uptake and growth control. One method involves a dose‐response study of the effect of a mitogen on uptake and DNA synthesis, while a second method involves search for a particular mitogen that may, under the appropriate conditions, stimulate cell division without stimulating uptake. These two methods are limited, however, since they are not always applicable to any given nutrient or mitogen. A third method which is not limited in its applications involves varying the concentration of a particular nutrient in the medium to control its uptake. In the case of orthophosphate (Pi) or glucose, we have used this “nutrient concentration” method to demonstrate that under normal culture conditions, uptake of these nutrients is not a causal event in the regulation of cell division.We considered the possibility that intracellular nutrient availability might control cell growth, even under conditions where uptake did not. For Pi and glucose, we assumed intracellular pool size to be an accurate indicator of intracellular nutrient availability and measured these pools under a variety of proliferative conditions. These studies revealed, however, no correlation between pool size and proliferative state of the cells. This clearly demonstrates that for Pi and glucose, intracellular pool sizes are not causally involved in the control of growth. The possibility remains, however, that if these nutrients are compartmentalized within the cell, intracellular pool sizes may not be an accurate indicator of nutrient availability.For Pi and glucose there are many interesting questions that remain to be answered about the transport mechanisms for these nutrients. For some other nutrients, particularly K+ and amino acids, in addition to questions dealing with the nature of transport mechanisms, the question of uptake involvement in the control of proliferation remains entirely open. As with Pi and glucose, many observations strongly suggest a fundamental relationship between amino acid or K+ uptake and control of cell growth. We suggest that the “nutrient concentration” technique used in our studies to analyze Pi and glucose uptake is applicable to any nutrient and should, therefore, prove extremely useful for studying the involvement of any uptake change in the regulation of cell proliferation.