BH3-only proteins Puma and Bim are rate-limiting for γ-radiation and glucocorticoid-induced apoptosis of lymphoid cells in vivo

Numerous p53 target genes have been implicated in DNA damage-induced apoptosis signaling, but pro-apoptotic Bcl-2 family members of the BH3-only subgroup appear to play the critical initiating role. In various types of cultured cells, three BH3-only proteins, namely Puma, Noxa and Bim, have been shown to initiate p53-dependent as well as p53-independent apoptosis in response to DNA damage, treatment with anti-cancer drugs or glucocorticoids. In particular, the absence of Puma or Bim renders thymocytes and mature lymphocytes refractory to varying degrees to death induced in vitro by growth factor withdrawal, DNA damage or glucocorticoids. To assess the in vivo relevance of these findings, we subjected mice lacking Puma, Noxa or Bim to whole body γ-radiation or the glucocorticoid dexamethasone and compared lymphocyte survival with that in wild type and bcl-2 transgenic mice. Absence of Puma or Bcl-2 overexpression efficiently protected diverse types of lymphocytes from the effects of γ-radiation in vivo and loss of Bim provided lower but significant protection in most lymphocytes, whereas Noxa-deficiency had no impact. Furthermore, both, Puma and Bim, were found to contribute significantly to glucocorticoid-induced killing. Our results thus establish that Puma and Bim are key initiators of γ-radiationand glucocorticoid-induced apoptosis in lymphoid cells in vivo. For personal use only. on October 28, 2017. by guest www.bloodjournal.org From