RELATIONSHIP BETWEEN p53/p21/Rb AND MAPK SIGNALING PATHWAYS IN HUMAN ENDOMETRIUM-DERIVED STEM CELLS UNDER OXIDATIVE STRESS
P.I. Deryabin, A.V. Borodkina, N.N. Nikolsky, E.B. Burova 1
Institute of Cytology RAS, St. Petersburg, 194064;
1 e-mail: lenbur87@mail.ru
Human endometrium-derived mesenchymal stem cells (hMESC) under the sublethal oxidative stress induced by Í2Î2 activate both p53/p21/Rb and
p38MAPK/MAPKAPK-2 pathways that are responsible for the induction of hMESC premature senescence (Borodkina et al., 2014). However the mutual relations between p53/p21/Rb
and MAPK signaling pathways, including ERK, p38 and JNK remain unexplored as yet. Here, we used the specific inhibitors - pifithrin-α (PFT), U0126, SB203580 and SP600125
to "switch off" one of the proteins in these cascades and to evaluate the functional status alterations of the rest proteins. Suppression each of the MAPK significantly increased the
p53 phosphorylation levels, as well as p21 protein expression followed by Rb hypophosphorylation. On the other hand, PFT-induced p53 inhibition enhanced mostly the ERK1/2
activation compared with p38 and JNK. These results suppose the existence of the reciprocal negative regulation between p53- and MAPK-dependent signaling pathways. Analyzing
the possible interactions among the members of the MAPK family, we showed that p38 and JNK can function as the ERK antagonists: JNK is capable to activate ERK, while p38 may
block the ERK activation. Together, these results demonstrate complex links between different signaling cascades in stressed hMESC, implicating ERK, p38 and JNK in regulation
of the premature senescence via p53/p21/Rb pathway.
Key words:
premature senescence, MAPK, pifithrin-α, p53, endometrial stem cells, oxidative stress, signaling pathways
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