The effect of small-molecule inhibition of MAPKAPK2 on cell ageing phenotypes of fibroblasts from human Werner syndrome.

[werner syndrome]

Fibroblasts derived from the progeroid Werner syndrome (WS ) show reduced replicative lifespan and a "stressed " morphology , both phenotypes being alleviated by using the p 38 MAP kinase inhibitor SB 203580 . Because p 38 is a major hub for the control of stress-signalling pathways we were interested in examining the possible role for downstream kinases in order to refine our understanding of the role of p 38 signalling in regulation of WS cell growth . To this end we treated WS and normal fibroblasts with MK 2 inhibitors to determine whether MK 2 inhibition would affect either the growth or morphology of WS cells . The first inhibitor , 7 ,8 -dihydroxy-2 ,4 -diamino-3 -cyanobenzopyranopyridine (inhibitor 2 ), resulted in inhibition of WS cell growth and had no effect on morphology , effects that occurred below the level needed to inhibit MK 2 and thus suggestive of inhibitor toxicity . The second inhibitor , 2 -(2 -quinolin-3 -ylpyridin-4 -yl )-1 ,5 ,6 ,7 -tetrahydro-4 H-pyrrolo-[3 ,2 -c ]pyridin-4 -one (CMPD 16 ), resulted in a significant extension of WS fibroblast replicative capacity compared to normal cells . In addition , CMPD 16 reverted the WS cellular morphology to that seen in normal dermal fibroblasts . These data suggest that MK 2 activity plays a substantial role in proliferation control in WS cells . CMPD 16 was not as effective in cellular lifespan extension as SB 203580 , however , suggesting that , although MK 2 is a downstream kinase involved in cell cycle arrest , other p 38 targets may play a role . Alternatively , as CMPD 16 is toxic to cell growth at levels just above those that extend lifespan , it is possible that the therapeutic window is too small . However , as CMPD 16 does show significant effects in WS fibroblasts , this acts as proof-of-principle for the efforts to design and synthesise improved MK 2 inhibitors . As MK 2 is involved in inflammatory processes and inflammation plays a major role in WS phenotypes , these data suggest MK 2 as a potential therapeutic target for the treatment of Werner syndrome .

Diseases
Validation

Diseases presenting "2" symptom

22q11.2 deletion syndrome

cushing syndrome

epidermolysis bullosa simplex

erythropoietic protoporphyria

krabbe disease

monosomy 21

pendred syndrome

thoracic outlet syndrome

trochlear dysplasia

werner syndrome

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