Female tissue specific cancers such as breast, endometrial, uterine and ovary account for over 3,000,000 cancer related incidents annually advancements in therapeutics and treatment however require a deeper understanding of the molecular aetiology associated with these diseases. Recent studies suggest a possible role of p38β in both breast and endometrial cancer with research suggesting involvement in bone metastasis and cancer cell survival. However, the mechanistic role of the isoform, p38β, remains fairly elusive. The widely studied p38α isoform is ubiquitously expressed and is implicated in a number of cancer pathologies, as are p38γ and p38δ. further demonstrate that mutation of either glycosylation site of irisin compromised its activity whether this is due to a strict requirement of these modifications for (putative) receptor binding or whether they influence protein folding/solubility was not addressed.The p38MAPK family of Mitogen Activated Protein Kinases are a group of signalling molecules involved in cell growth, survival, proliferation and differentiation. Further studies will illustrate how the expression and activation of this receptor is regulated under physiological (exercise) and/or pathological (metabolic diseases) conditions. The swift response and the evidence that irisin directly binds to the cell membrane alludes to a yet-to-be-identified irisin receptor present in both primary inguinal cells and 3T3-L1 cells. The signal transduction through ERK and p38 occurs within 20 min after irisin is added to the cell culture. While both of these kinases have been implicated previously in the thermogenic actions of other agents on brown fat, including β-adrenergic agonists and FGF21, the role in irisin action was not known ( 11, 24, 25). The article shows rather convincingly that these browning effects depend on the activation of extracellular signal–related kinase (ERK) and p38 protein kinase signaling cascades. The effects on the 3T3-L1 cultures are especially impressive because these cells are generally viewed as very “white,” or not prone to the induction of mRNA encoding UCP1 and other thermogenic genes. This article used the mammalian irisin produced in yeast cells and found that it is both heavily glycosylated and biologically active when placed on either 3T3-L1 cells or primary cultures from the rat inguinal depot. ( 23) addressed the signal transduction pathways by which irisin drives the browning of white fat cells. Because the human irisin mRNA has an AUA start codon in the precise location where other species have a classical ATG start codon, the possibility that the human gene might not encode a protein has been raised ( 17), though the large number of studies measuring human irisin in blood with different antibodies and methods would seem to close this issue ( 15, 16, 18– 22). Interestingly, two articles report that human patients with diabetes are deficient in irisin compared with normal counterparts ( 15, 16). Regarding human irisin, it is clear that FNDC5 mRNA is increased in skeletal muscle in some exercise paradigms but not others ( 2, 13, 14). This correlates with improvements in glucose tolerance in obese mice. Irisin appears to act preferentially on the browning of white fat deposits when elevated in the blood of obese mice via viral vectors. The parent polypeptide, FNDC5, is synthesized as a type 1 membrane protein and is then cleaved and shed into the circulation as a highly glycosylated polypeptide of roughly 12kDa. Irisin was of interest because it is induced during exercise in rodents and is at least partially responsible for the browning response observed in white fat during chronic exercise ( 2). Several polypeptides, including FGF21, BMP7/8b, BNP/ANP, and orexin, all have interesting browning effects ( 8– 12). The confirmed presence of UCP1 + brown fat in humans has added to the interest in finding methods and molecules that can augment energy expenditure through browning of beige fat cells ( 5– 7). In fact, the improvements seen in glucose tolerance observed with “browning” of white fat and the formation of “beige” or “brite” cells might be greater than expected solely from their effects on body weight and adiposity ( 4). These cells express UCP1 and have a high mitochondrial content, thereby dissipating chemical energy in the form of heat. That brown fat, in all of its dimensions, can improve type 2 diabetes and metabolic health seems to be settled science, at least in experimental animals ( 3).
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