Abstrakt
Protein p53 plays an essential role in the induction of apoptosis by ionizing radiation in haemopoietic cells, the damage of which is the main reason for the development of bone marrow post-irradiation syndrome. p53 activation leads to an increase in the Bcl-2 family pro-apoptotic protein PUMA level. PUMA inhibits all the five anti-apoptotic proteins (Mcl-1, Bcl-2, Bcl-X-L, Bcl-W and A1) and directly triggers apoptosis mediated by pro-apoptotic proteins Bax/Bak.
In proliferating cells, knockout of p53 inhibits apoptosis on the one hand, but on the other disables the cellular division arrest moderated by p21(Cip1/Waf1). The radioprotective effect of p53 inhibitor pifithrin was obvious at radiation doses causing the bone marrow syndrome.
Knockout of PUMA also exerts its radioprotective effect through blocking the apoptosis induction, but the arrest of cells in the cell cycle through p21 induction is not abolished. PUMA -/- mice are radioresistant in terms of the development of post-irradiation syndrome after all radiation doses.
Small molecules are being searched for that could prevent binding of PUMA with Bcl-2 family anti-apoptotic proteins. This would result in apoptosis inhibition and radioprotective or mitigating effects of these inhibitors.