Influence of FOX genes on aging and aging-associated diseases. Elena Tschumak
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Название: Influence of FOX genes on aging and aging-associated diseases
Автор: Elena Tschumak
Издательство: Bookwire
Жанр: Медицина
isbn: 9783754131572
isbn:
According to Alessandro et al., (2015) MET positively influences decreased mitochondrial transmembrane potential, sensitivity to TRAIL via DR5-upregulation, ROS-level and cell cycle in cancer via miR-221 (Tanaka et al., 2015 Matsubara et al., 2013) but also via TRAIL interaction. In this case G-Phase arrest happens via p27Kip-1 and via interaction between caspases (Coleman et al., 2013) Other plant-derived cancer relevant chemicals are e.g. SHH pathway regulating catechins cyclopamine, norcantharidin, sulforaphane and zerumbone (Huang et al., 2013) They act best in combination and suppress ALDH1, MMP-2 and MMP-9 via KRAS under- and let7 miR- upregulation. (Appari et al., 2014) Momordica charantia has positive effect on inflammation and on cancer (Dandawate et al.,2016), e.g. on ovarian cancer via of AMPK up-, mTOR/p70S6K and AKT/ERK/FOXM1 signalling cascade underregulation (Yung et al., 2016) possibly via Alpha-Momorcharin (Deng et al., 2014).
Also Rooperol influences apoptosis with the help of mitochondrial membrane potential. It upregulates ROS via TP53 activation, but also OCT4 and stemness relevant SOX2 and NANOG (Ali et al., 2015) It also increases Pomiferin level, which influences BIM1 and NESTIN (Zhao et al., 2013)
FOXP1, FOXP2 and FOXP4 are of great importance for alpha cell proliferation and function and are expressed in the pancreas and eyes of Xenopus laevis during its development. FOXA1 and FOXA2 also regulate glucagon production and secretion-controlling genes: the MAFB, the Brn4 (also known as the Pou3f4), the PCK2, the Nkx2-2, the Kir6.1 (also known as the Kcnj8), the Sur1 (also known as the ABCC8) and the GIPR.
FOXP2 regulation by external factors Regulation by PH level Blane and Fanucchi (2015) studied in "Effect of pH on the Structure and DNA Binding of the FOXP2 Forkhead Domain." effects of pH from changes 5 to 9 on FOXP2 function and reported that a change in pH (pH 7.5) directly affects the FOXP2 binding affinity via the altered hydrogen bonding pattern. This is due to the protonation or deprotonation of His554 (the amino group of its imidazole side chain, pKa ~ 6.5). The researchers used as methods gel permeation chromatography, ultraviolet circular dichroism, intrinsic and extrinsic fluorescence etc. Their results showed that the pH does not affect the protein secondary structure in the presence or absence of DNA but alters its tertiary structure. The protein showed a less compact structure at low pH in the absence of DNA. When the DNA was added, the protein became more compact, even at low pH and its dimerization potential increased. They regarded the pH as a regulatory mechanism of FOXP2 forkhead domain (FHD) transcription that interacts with the DNA by helix placement in the major groove. These results could also be important in cancer tissue, where FOXP2 expression plays an important role. E.g., not only the genetic component but also a previous chronic gastric ulcer with changed pH plays a significant role in gastric cancer. The gastric ulcer-causing Helicobacter pylori gains an almost pH-neutral environment with the help of the enzyme urease, which splits the urea into carbon dioxide and ammonia. It would be of great scientific interest to investigate whether the change in the gastric pH together with FOXP2 have an effect on the development of gastric cancer.
Regulation through Vitamin-D
Hawes et al. (2015) showed in „Maternal vitamin D deficiency age foetal brain development in the BALB / c mouse“ how the maternal vitamin D deficiency alters foetal brain development in transgenic Balb / c mice. Before and during pregnancy a vitamin D-rich (2.195 IU / kg) or a low (0 IU / kg) diet was given for 5 weeks and the foetal brains were analysed morphologically and for gene expression at 14.5 or 17.5. embryonic day. It was found that the vitamin D deficiency during pregnancy leads to reduction of rump length, lateral ventricle volume and head size. The FoxP2 expression and at the same time the expression of Brain-Derived Neurotrophic Factor (BDNF), the Transforming growth factor-β1 (TGF-β1) and brain tyrosine hydroxylase (TH) in dopaminergic neurons was altered. The vitamin D-poor diet reduced FOXP2 expression in immunoreactive cells and in the developing cortex in female foetuses. These results allowed deeper insight into the medically relevant reasons for foetal degeneration accompanied by prenatal vitamin D deficiency. It is known that vitamin D interacts with neurotrophic factors (NGF, NT3, NT4, GDNF) and its deficiency triggers neurodegenerative diseases in old age. (Jia et al, 2015) It would be of great interest to investigate if this effect is based on the interaction with FOXP2. Since FOXP2 seems to play an important role in many oncological diseases it would be also interesting to investigate if and to what extent this influence is controlled by vitamin D.
FOXP2 regulation by internal factors Regulation by HuR According to Popovitchenko et al. (2016) „Depending on its degree of phosphorylation, the antigen R (HuR) dictates the amount of FOXP2 mRNA and the development of the neocorticals controlled by it, depending on its degree of phosphorylation“ HuR is the main factor in differential translation of autism-associated FoxP subfamily members in the developing neocortex subpopulation of the projection neurons. Regulation by Risperidone and NAP The study of a big Scottish family with severe mental disorders and schizophrenia (Liu et al. 2009) showed a balanced chromosomal translocation [(1:11) (q42.1; q14.3)] and an abnormally-truncated DisC1 protein (a microtubule-regulating and the FOXP2-influenced protein encoded on chromosome 1). The DISC1 is expressed in the cerebral cortex, in the hypothalamus, in the amygdala, in the hippocampal dentate gyrus, in the olfactory bulb and in the cerebellum. The truncated human DISC1 (hDISC1) alters its localization and can no longer interact with microtubules and microtubule-associated proteins. It leads to decreased dendritic growth and branching. Such anomalies have also been found in brain samples from patients with schizophrenia. (Harrison, 2004) This mutation has also been linked to depression and bipolar disorder. (Burdick et al., 2005) A connection between DISC1 and FOXP2 effects human verbal fluency as well as the ability to acquire spoken language. Several studies indicate that FOXP2 polymorphisms are in some cases associated with schizophrenia. (Nicodemus et al., 2014), (Walker et al., 2012), (Lai et al., 2001), (MacDermo et al., 2005), (Sanjuan et al., 2005), (Sanjuan et al. , 2006), (Tolosa et al., 2010) Vaisburd et al. (2015) showed in „Risperidone and NAP protect cognition and normalize gene expression in a schizophrenia mouse model“ that risperidone reduces effects of the DISC1 mutation. Risperidone is an analogue of the microtubule-stabilizing activity-dependent neuroprotective protein (ADNP) with a NAP (NAPVSIPQ) sequence and a SxIP motif (a microtubule junction for microtubule-end binding, responsible for microtubule dynamics and this is also important for synaptic plasticity and neuroprotection). (Oz et al., 2014), (Gozes et al., 2011), (Holtser-Cochav et al., 2006), (Jouroukhin et al., 2013), (Kumar & Wittmann, 2012).
Both risperidone and NAP improved object recognition in the Morris water labyrinth. In contrast to Risperidone, NAP additionally reduced the anxiety in transgenic mice. Doxycycline blocked the expression of the mutated DISC1 gene. The candidate drugs were selected using bioinformatics programs and then affinity chromatographed. Mutations of the DISC1 gene were associated with increased FOXP2 level in hippocampus. FOXP2 levels could be significantly reduced by treatment with NAP, risperidone or their combination. This effect may be due to the blocking of the dopamine and 5HC2A serotonin receptors in the mesolimbic system, which leads to the reduction of negative schizophrenia symptoms. (Meltzer and McGurk, 1999), (Farde et al., 1995)
An increased dopamine level leads to psychotic symptoms. The study by Mendoza et al. (2015), showed that FoxP-expressing neurons in Area-X also contain dopamine receptors 1A, 1B, and 2. Further studies may clarify whether the schizophrenic positive symptoms are due to the dopamine-FOXP2 interaction and how much FOXP 2 can influence dopamine dependent neurodegeneration in aging.
Regulation of FOXP2 and other FOXP genes by SUMOilization
Effect of sumoilization on the СКАЧАТЬ