MAPKAPK2-Deletion führt zur partiellen Normalisierung des sekretorischen Phänotypen in Telomer-dysfunktionellen Mäusen ohne Auswirkung auf Organerhalt und Überleben
FacultiesFakultät für Naturwissenschaften
LicenseStandard (Fassung vom 01.10.2008)
With successive telomere shortening late generation Telomerase knockout mice prematurely develop aging symptoms like a senescence-associated secretory phenotype, myeloproliferation, reduced body weight, crypt atrophy in the intestine and have a shortened life expectancy. A candidate molecule for mediating these aging symptoms is MK2, a direct target of the MAP kinase p alpha/ß. Besides regulating several cytokines and other mediators, its participation in hematopoiesis and inflammatory diseases, as wells as its contribution to DNA damage signaling and cell cycle arrest, MK2 could also be involved in metabolism. To this end the influence of MK2 on accelerated aging due to telomere shorting has been analyzed in the mouse model of telomerase and MK2 double knockout. We hypothesized that elimination of MK2 could prevent activation of p53/p21 after telomere-shorting induced DNA damage leading to senescence and apoptosis and thereby prevent tissue damage, but could not confirm this hypothesis. Despite reduced activation of p53/p21 in the intestinal epithelium of double knockout mice the intestine was structurally damaged. The nutrient deficiency of Telomerase knockout mice, of which signs are increased growth hormone secretion and simultaneous growth hormone resistance, was exacerbated by loss of MK2 presumably as an effect of disturbed gluconeogenesis. Nevertheless, survival of Telomerase knockout mice was not altered by the absence of MK2. Nor could the systemic inflammation be improved by disruption of p38/MK2 signaling in Telomerase deficient mice, recognizable in the persisting biased cytokine environment and the prevalence of innate immune system cells. The reduction of inflammation factors in the blood plasma paralleled by an increase in growth hormone secretion by MK2 deficiency did not prevent the development of granulocytosis seen in the Telomere dysfunctional background, although splenomegaly could be prevented by reduction of hematopoietic cell proliferation.
Subject HeadingsTelomerase [GND]
Aspartic acid endopeptidases [MeSH]
MK2 protein, human [MeSH]