Since all organisms carry on cellular ..
As a cell approaches the end of the G1 phase it is controlled at a vital checkpoint, called G1/S, where the cell determines whether or not to replicate its DNA. At this checkpoint the cell is checked for DNA damage to ensure that it has all the necessary cellular machinery to allow for successful cell division. As a result of this check, which involves the interactions of various proteins, a "molecular switch" is toggled on or off. Cells with intact DNA continue to S phase; cells with damaged DNA that cannot be repaired are arrested and "commit suicide" through apoptosis, or programmed cell death. A second such checkpoint occurs at the G2 phase following the synthesis of DNA in S phase but before cell division in M phase. Cells use a complex set of enzymes called kinases to control various steps in the cell cycle. Cyclin Dependent Kinases, or CDKs, are a specific enzyme family that use signals to switch on cell cycle mechanisms. CDKs themselves are activated by forming complexes with cyclins, another group of regulatory proteins only present for short periods in the cell cycle. When functioning properly, cell cycle regulatory proteins act as the body's own tumor suppressors by controlling cell growth and inducing the death of damaged cells. Genetic mutations causing the malfunction or absence of one or more of the regulatory proteins at cell cycle checkpoints can result in the "molecular switch" being turned permanently on, permitting uncontrolled multiplication of the cell, leading to carcinogenesis, or tumor development.
rate of protein synthesis and ..
"It's a scenario of gradual accretion in a world that is very much like the one of today that has nucleic acids and proteins." Although molecular biologist Russell Doolittle of the University of California, San Diego, who was not involved in the study, praised the work, he also expressed curiosity about how early proteins could be synthesized before the ribosome existed.
Fatty acids could impact protein metabolism by their effect on the insulin signaling pathway, resulting in insulin resistance (). A number of physiological and pathological states are accompanied by the appearance of insulin resistance, defined as a decrease in uptake of glucose, primarily by the skeletal muscle, in response to prevailing insulin levels. Insulin resistance is considered to play a major role in the development of type 2 diabetes. Although a number of studies have examined the impact of insulin resistance on carbohydrate and lipid metabolism, there is a paucity of data in relation to its effect on protein metabolism. Increased nitrogen accretion in physiological states such as puberty, pregnancy, and possibly growing infants, and during pharmacological intervention by GH, is characterized by the development of insulin resistance by diverse mechanisms (,,,). The development of insulin resistance during pregnancy is a critical physiological response for the growth of the fetus. The birth weight of the neonate is positively correlated with the magnitude of insulin resistance in the mother (,). Pathological states such as chronic renal failure, cirrhosis of the liver, and sepsis are also associated with insulin resistance (,). The biological role of insulin resistance in these conditions is unclear, but it may be aimed at accretion and preservation of lean body mass. The relative contribution of other factors that can cause insulin resistance, such as counterregulatory hormones like glucagon, catecholamines, GH, or the pregnancy-related hormones, and cytokines such as TNFα, may vary in these conditions. Nevertheless, in several of these states, an elevated concentration of plasma fatty acids is consistently seen. More than 35 yr ago, Randle () and colleagues, based upon a series of studies on skeletal muscle in vitro, had proposed a competition between oxidative substrates, i.e. fatty acid and glucose. The mechanism of this so-called glucose-fatty acid cycle or substrate competition has been an area of intense scrutiny and now has been related to impaired insulin action. As proposed by Shulman () and colleagues, based upon extensive data in humans and in animal models, increased delivery of fatty acids to the muscle (fatty acid overload) leads to an increase in the products of fatty acid metabolism, e.g. long chain fatty acyl coenzyme A, diacylglycerol, ceramides, etc. These metabolites, in particular diacylglycerol, activate serine-threonine phosphorylation cascades initiated by protein kinase C, leading to phosphorylation of the serine/threonine site on insulin receptor substrates (IRS1 and IRS2). This, in turn, reduces the ability of IRS to activate phosphoinositide 3-kinase. Phosphoinositide 3-kinase is considered the key branch point for a number of downstream signaling pathways for protein synthesis, for cell growth, and for glycogen synthesis. Our understanding of the regulation and control of these signaling pathways continues to grow exponentially, leading to identification of isoforms of these signaling proteins and their differential regulation in response to various signals (,). A decrease in the activity of the insulin signaling cascade as a result of fatty acid load would be expected to attenuate the insulin-induced response to protein synthesis via the downstream protein kinase B (also known as AKt) and target of rapamycin signaling pathway. However, the data of Katsanos et al. () showed that even in the presence of fatty acid-induced insulin resistance, the protein synthesis response to amino acid load was not impaired. Studies in healthy humans have shown that amino acids stimulate skeletal muscle protein synthesis through an AKt-independent pathway (,). This effect is more evident with branched-chain amino acids, specifically with leucine. The stimulation of protein synthesis has been identified to be via activation of target of rapamycin, which in turn activates p70S6 kinase and dephosphorylates 4EBP-1 (eIF4E-binding protein 1), leading to translation initiation, protein synthesis, and protein metabolism. Additional downstream effects of amino acids independent of insulin signaling have been suggested (). However, the stimulatory effect of amino acids is not seen in the total absence of insulin in vivo, due in part to the counterregulatory responses to the lack of insulin.