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      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, Berberine, EGCG, quercetin and other natural products activate cancer relevant AMPK and decrease mTORC1 activity. MTORC1 activity is frequently elevated in CSC including pancreatic CSCs (Ming et al., 2014; Rozengurt et al., 2014; Matsubara et al., 2013) EGCG also positively effects cancer and aging relevant p21Cip1 and negatively the PI3K/PTEN/Akt/mTORC1 pathway (Chen et al., 2012)

      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.