Nuclear transcription factors

Finally, it has to be mentioned that LPA also has an intracellular target site, which is the nuclear transcription factor, peroxisome proliferator-activated receptor-y (PPARy). LPA competes for thiazolidinedione binding and activates PPARy-dependent gene transcription. Thereby, LPA induced neointima formation in a rat carotid artery model. 

These agents activate PPAR-y a nuclear transcription factor important in fat cell differentiation and fatty acid metabolism. PPAR-yagonists enhance insulin sensitivity in muscle, liver, and fat tissues indirectly. Insulin must be present in significant quantities for these actions to occur. 

As was mentioned earlier, DAG activates protein kinase C, which phosphorylates transcription factors like NFjcB nuclear transcription factor. NFjcB forms a multisubunit complex with an inhibitory subunit which is phosphorylated by PKC. The complex disintegrates and what is released translocates to the nucleus and initiates gene transcription. NFjcB is a heterodimer, with two distinct DNA-binding subunits 50 kDa and 65 kDa, both being members of the Rel transcription factor family. These proteins have an important role in the signaling cascade of the cellular defense system, and activate numerous genes in response to pathogens or inflammatory cytokines. 

Manna SK, Sarkar S, Barr J, Wise K, Barrera EV, Jejelowo O, Rice-Ficht AC, Ramesh GT (2005) Single-walled carbon nanotube induces oxidative stress and activates nuclear transcription factor-kappa B in human keratinocytes. Nano Lett. 5 1676-1684. 

Shimohata T, Onodera O, Tsuji S (2000) Interaction of expanded polyglutamine stretches with nuclear transcription factors leads to aberrant transcriptional regulation in polyglutamine diseases. Neuropathology 20(4) 326-333... 

Finally, inappropriate expression of nuclear transcription factors can lead to cell transformation. For example, the products of he,fos and myc proto-oncogenes are transcription factors that regulate the expression of proteins that promote progression through the cell cycle. Levels of the Fos and Myc proteins are tightly regulated in normal cells. Uncontrolled expression of these proteins leads to cell proliferation. 

Fig. 3.6. Principles of signal transduction by transmembrane receptors and nuclear receptors, a) transmembrane receptors receive the signal on the cell surface and convert it into an intracellular signal that can be passed on until it reaches the nucleus, b) In signal transduction via nuclear receptors the hormone enters the cell and binds the receptor either in the cytosol (R) or nucleus (R ). Nuclear receptors act as nuclear transcription factors that bind specific DNA elements (HRE hormone responsive element) found in the promotor region of regulated genes to control their transcription rate.

ERK moves into the nucleus and phosphorylates nuclear transcription factors such as Elkl, activating them. 

Regulation Can Result from Phosphorylation of Nuclear Transcription Factors... 

Recent studies revealed that resveratrol protects from inflammation by acting at different phases of inflammation. Protection at the pro-inflammatory phase appears to be very important for reducing inflammation effectively and promptly. A recent study [Ge et al., 2006] showed that resveratrol inhibits macrophage expression of EMMPRIN by activating PPAR-y. In another similar study, Ma et al., [2006] showed a similar observation, but additionally found a role of nuclear transcription factor kB (NF-kB) in macrophage inhibition. Numerous studies confirmed that resveratrol suppresses the TNF-a... 

Estrov Z, Shishodia S, Faderl S, Harris D, Van Q, Kantarjian HM, Talpaz M, Aggarwal BB. 2003. Resveratrol blocks interleukin-1 beta-induced activation of the nuclear transcription factor NF-kB, inhibits proliferation, causes S-phase arrest, and induces apoptosis of acute myeloid leukemia cells. Blood 102 987-995. 

Manna SK, Mukhopadhyay A, Aggarwal BB. 2000. Resveratrol suppresses TNF-induced activation of nuclear transcription factors NF-k B, activator protein-1, and apoptosis Potential role of reactive oxygen intermediates and lipid peroxidation. J Immunol 164 6509-6519. 

Yoneda Y., Kuramoto N., Kitayama T., and Hinoi E. (2001). Consolidation of transient ionotropic glutamate signals through nuclear transcription factors in the brain. Prog. Neurobiol. 63 697-719. 

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