Mitogenic effect

Fluorid ions stimulate bone formation by a direct mitogenic effect on osteoblasts mediated via protein kinase activation and other pathways. Further to these cellular effects, fluorides alter hydroxyapatite crystals in the bone matrix. In low doses, fluorides induce lamellar bone, while at higher doses abnormal woven bone with inferior quality is formed. The effect of fluorides on normal and abnormal (e.g. osteoporotic) bone therefore depends on the dose administered. 

Goligorsky, M.S., Morgan, M.A., Suh, H., Safirstein, R and Johnson, R (1992). Mild oxidative stress, cellular mode of mitogenic effect. Renal Failure 14, 385-389. 

The cytoplasmic domain of the P-subunit displays three distinct sub-domains (a) the juxtam-embrane domain , implicated in recognition/binding of intracellular substrate molecules (b) the tyrosine kinase domain, which (upon receptor activation) displays tyrosine kinase activity (c) the C-terminal domain, whose exact function is less clear, although site-directed mutagenesis studies implicate it promoting insulin s mitogenic effects. 

Investigations of the cellular effects of radiofrequency radiation provide evidence of damage to various types of avian and mammalian cells. These effects involve radiofrequency interactions with cell membranes, especially the plasma membrane. Effects include alterations in membrane cation transport, Na+/K+-ATPase activity, protein kinase activity, neutrophil precursor membrane receptors, firing rates and resting potentials of neurons, brain cell metabolism, DNA and RNA synthesis in glioma cells, and mitogenic effects on human lymphocytes (Cleary 1990). 

Experimental studies showed antitumoral effects of raloxifene in different in vitro preparations and animal models. Raloxifene has been able to inhibit the mitogenic effect induced by estrogens on ZR-75-1 cells, an estrogen responsive human breast cancer cell line (Poulin et al. 1989). In a well-accepted rat model of breast cancer induced by nitroso-methyl urea (NMU) raloxifene significantly suppressed the development of breast tumors and acted synergistically with 9 cis-retinoic acid (Anzano et al. 1996). 

Fu, Y. and Blankenhom, E.R, Nitric oxide-induced anti-mitogenic effects in high and low responder strains, J. Immunol., 148, 2217, 1992. 

DNA synthesis, gene expression and growth promotion (mitogenic effects) (all cells) ... 

Mitogenic effects are mediated through MEK/MAPK (mitogen-activated protein kinase) and changes in metabolic activity mainly via PI3K. 

Roth A, et al. Synthesis of thiol-reactive lipopeptide adjuvants. Incorporation into liposomes and study of their mitogenic effect on mouse splenocytes. Bioconjugate Chem 2004 15 541. 

SEA (Leu-48-Gly) and SEB (Phe-44-Ser) mutants unable to bind major histocompatibility complex class II remain emetic but lack T-cell mitogenic effects. " A disulfide loop in SEs, which is absent in the non-enterotoxic TSST-1, may be responsible for the emetic activity of SEs but that too remains controversial. Carboxymethylation of histidines on SEA or SEB generates superantigenic molecules devoid of enter-otoxicity or skin reactivity. This chemically modified SEB also inhibits, perhaps in a competitive fashion, the... 

A nonlinear approach should be selected when there are sufficient data to ascertain the mode of action and to conclude that it is not linear at low doses, and the agent does not demonstrate mutagenic or other activity consistent with linearity at low doses. The POD is in this case generally a BMDL when incidence data are modeled. A sufficient basis to support this nonlinear procedure is likely to include data on responses that are key events in the carcinogenic process. This means that the POD may be based on these precursor response data, for example hormone levels or mitogenic effects, rather than tumor incidence data. A nonlinear approach can be used to develop an RfD or an RfC. This approach expands such reference values, previously reserved for threshold effects, to include carcinogenic effects determined to have a nonlinear mode of action. A nonlinear approach should generally not be used in cases where the mode of action has not been ascertained. 

In the human female, IGF-1 is expressed by follicular theca cells, while IGF-2 is synthesized by granulosa cells (Chapter 8). The IGF-1 and -2 receptors are widely expressed in ovarian tissue, and synthesis of both growth factors and their receptors are influenced by circulating gonadotrophin levels. IGF-1 exerts a direct mitogenic effect on human granulosa cells, and promotes increased androgen and oestradiol synthesis by these cells. IGF-1 also promotes increased expression of FSH and LH receptors in ovarian tissue. 

Two processes have been proposed to explain the mitogenic effect of fluoride on bone cells involving either fluoride ions directly or the AIF complex (Fig. 11). Fluoride ions have been shown to directly inhibit an enzyme (tyrosine phophory-lase phosphatase) resulting in an enhancement of the tyrosine phosphorylation part of the mitogen-activated protein kinase system (MARK) [177], The other activation pathway involves a complex of aluminium and fluoride which activates the G-protein and stimulates tyrosine phophorylation resulting in an enhanced mitogenic effect [176]. 

The mitogenic effect of lipopolysaccharide on bone marrow-derived mouse lymphocytes. Lipid A as the mitogenic part of the molecule. J. Exp. Med., 137, 943-953... 

Plouet, J., Moro, F., Bertagnohi, S., Coldeboeuf, N., Mazarguil, H., Clamens, S. and Bayard, F. (1997) Extracellular cleavage of the vascular endothelial growth factor 189-amino acid form by urokinase is required for its mitogenic effect. J. Biol. Chem., 272,13390- 13396. 

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