Influence of FOX genes on aging and aging-associated diseases. Elena Tschumak
Чтение книги онлайн.
Читать онлайн книгу Influence of FOX genes on aging and aging-associated diseases - Elena Tschumak страница 12
Название: Influence of FOX genes on aging and aging-associated diseases
Автор: Elena Tschumak
Издательство: Bookwire
Жанр: Медицина
isbn: 9783754131572
isbn:
HFS diet showed neuroprotective affects, via miR-21 miR-22, miR-34 and miR-101, wich decreases expression of E2F3 and SIRT1 (Kumazaki et al., 2013) , but also via miR-146a, miR-200 and let-7.
Interestingly anti-aging natural products isoflavone, (-)-epigallocatechin-3-gallate, 3,3′-diindolylmethane, indole-3-carbinol, Curcumin positively affects Alzheimer, cardiovascular diseases, atopic asthma, Crohn’s disease, acute and chronic kidney injury, myeloma, glioblastoma, chronic lymphocytic leukaemia, cell lymphoma, osteosarcoma, colo-rectal-, breast-, non-small cell lung cancer and Helicobacter Pylori caused Ulcus. Berberine positively affects hyper-lipemia, cardiovascular diseases, diabetes, colorectal adenoma and Helicobacter pylori caused Ulcus too. It would be interesting to investigate if these effects are congruent with miR expression.
Structure and function of FoxP genes is responsible for his function
Structure of the FoxP2 gene and its isoforms
The FOXP2 gene is located on chromosome 7 and contains at least 280 (according to some data 603) kb, many introns (about 280,000 non-coding base pairs, according to a publication in 2007 - 603,000 base pairs), 7 exons ( 2145 coding base pairs), but their number is variable. (Zhang et al., 2002;Wright and Hastie, 2007)
The protein product of the FOXP2 gene consists of 715 amino acids and has the following domains: a highly conserved DNA-binding domain, a 508 to 584 amino acid "winged" helix domain (BHT) and the forkhead box with highly conserved two beta-sheets, three alpha helixes and a helix-turn-helix-motif-wing.
Structural variations occur between the second and third helix. The polyglutamine-rich regions with the repetitive CAG and CAA sequences show a high mutation rate as well as different length in different taxa. The FOXP2 gene has a zip finger involved in protein-protein interactions and a leucine zipper. The DNA binding in the minor and the major groove to various targets occurs between the third alpha helix (recognition helix) and the second wing of the FOX transcript. (Enard et al., 2002;Kaestner et al., 2000; MacDermot et al., 2005) The hinge loop plays the most important role in the FOXP2 protein binding to the target genes and the mutation P539A changes its form.(Morris et al., 2018)
Alternative splicing creates different FOXP2 isoforms and causes changes in FOXP2 activity. (Castellano and Downward, 2011). Depending on the tissue and cell type, FOXP2 expression can be started on at least 4 starting points (TSSs). (Bruce and Margolis, 2002; Schroeder and Myers, 2008).
Regulation of various genes by dimer formation with FOXP genes
FOXP2 cooperation and FOXP homo- and heterodimers A strong cooperation between FOXP members could be due to the fact that the FOXP2, FOXP1, FOXP3, and FOXP4 are 55-65% identical. A possible explanation for this similarity is proposed by Song et al. in "Genesis of the vertebrate FoxP subfamily member genesis during two ancestral whole genome duplication events" (2016). According to Murugan et al. (2013) decreased FoxP2 expression in the striatal region of adult zebra finches also interferes with their sensitivity to dopaminergic regulation in signalling via D1 receptors in Area-X, they also have co-localized dopamine D1A, D1B and D2 receptors in striatal Foxp2-expressing neurons. Dopamine is considered to be an important neurotransmitter whose deficiency causes some neurodegenerative diseases, e.g. aging relevant Parkinson's disease. This disease is characterized among other things by a washed-out language. It would be interesting to investigate if FOXP2 plays a role in these processes. The FoxP proteins can regulate their target genes in various cellular contexts depending on binding cofactor. Different protein combinations can lead to opposite effects. This could explain why certain tissues might be much more susceptible to the effects of mutations than other tissues. This study opened new perspectives in the regulation of FOXP2 target genes via protein-protein interactions between the FoxP family members, enabling a deeper understanding of the combinatorial control between the FoxP2 and its interaction partners. This study provided new basic knowledge not only about birdsong, but also about the neural function of human speech.
FOXP2 regulates the expression of many genes during embryonic development as well as the WNT and Notch signalling pathways. Further interactions have been observed with some histone family members (H2AFX; H3f3B) and two heat shock proteins (Hsp25; Hsp90a).
Importance of FOXP1/2/4 interaction for oncological processes Several FOXP genes have been observed in many aging relevant oncological processes. Foxp1 / 2/4-NuRD interaction is processed by the p66beta, a transcriptional repressor and a component of NuRD. During this process, the chromatin-remodelling complex regulates gene expression. He also influences the Interleukin-6. Interleukin-6 in turn contributes to the epithelial injury response and activates „myeloid cells“. The „myeloid cells“ are generally associated with cancer and stimulate eg. intestinal cells to divide, which leads to colorectal carcinoma. Artavanis-Tsakonas et al. (1999) studied NCOR2 and SNW1 as part of notch-mediated signalling and its role in proliferation and differentiation processes as well as in apoptosis. The NCOR2 is not only a FOXP2 downstream target but also shows interaction with FOXP1 during myocardial development. (Jepsen et al., 2008), (Wilke et al., 2012) NCOR2-mediated regulation can be considered as a common mechanism by which FOXP1 and other members of the FOXP family regulate gene expression during organogenesis. This study showed different effects of six FOXP1 / 2/4 protein combinations on the NCOR2. The FOXP1 / 2 combination showed the strongest effect. All combinations except the FOXP1 / 4 dimer led to increased NCOR2 expression. The FOXP2 homodimers induced decreased SNW1 expression while the FOXP1 and FOXP4 homodimers led to increased expression. The influence of FOXP1 / 2 and FOXP4 / 2 on SNW1 expression seems to be unlikely. These results gave an interesting insight into the dual FOXP2 function both as a repressor and as an activator. This ability for build different dimer-combinations may be a hint to fine-tune cell-specific transcriptional regulation. The FOXP1 / 2/4 dimer combinations are preferred. These results suggest that relative levels of FOXP1 / 2/4 proteins determine FOXP2's ability to act as an activator or repressor. The researchers found also that FOXP1 / 2, FOXP1 / 4 and FOXP2 / 4 are co-localized.
FOXP2 modulation by alternative splicing The FOXP is also regulated by alternative splicing. This way the FoxP2 gets different isoforms and is homodimerized and this leads to a change of its activity. (Santos et al., 2011) Similar results were reported by Chen et al. (2014) and Olias et al. (2013). This FOXP2 modification was observed in the lower and dorsal thalamus, in the striatum (except Area X) and in the cerebellar Purkinje cells. These are brain areas where the FoxP2 is permanent strongly expressed. (Takahashi et al., 2003), (Ferland et al., 2003), (Haesler et al., 2004) Epigenetic FOXP2 Regulation by Methylation FOXP2 methylation plays an important role by adipositas. Spaeth et al. showed in „The FOXP1, FOXP2 and FOXP4 transcription factors are required for islet alpha cell proliferation and function in mice“ (2015) that Foxp2 is important for the growth and function of pancreatic alfa islands. The islets of Langerhans of the exocrine pancreas contain five different cell populations: the beta, the alpha, the delta, the epsilon and the pancreatic polypeptide cells. These secrete the ghrelin and pancreatic polypeptide hormones (insulin, glucagon, somatostatin). The authors noted that interaction between FOXP2 and FOXP1 / FOXP4 is required for alpha-islet cell proliferation of the mice. Adult beta cells normally secrete insulin, the alpha cells - the glucagon. Autoimmune beta-cell destruction causes type 1 diabetes while type 2 diabetes is characterized by insulin resistance in the peripheral tissues. Type 2 diabetes is accompanied by insulin deficiency and the loss of beta cell identity. The transcription factors accomplish the reprogramming of terminally differentiated cells and embryonic stem cells into the beta-like cells. The members of the FOX superfamily play crucial roles in these processes, which is also aging relevant. E.g., FOXA2 is known as a pancreatic cell fate regulator. FOXM1 controls expression of cycle factors and increases beta cell mass during metabolic stress, including pregnancy stress and partial pancreatectomy. Metformin, СКАЧАТЬ