Down-regulation of wild-type p53 activity interferes with apoptosis of IL-3-dependent hematopoietic cells following IL-3 withdrawal.

Abstract

Overexpression of wild‐type p53 in p53‐deficient leukemic cells induces apoptosis, which can be inhibited by hematopoietic survival factors. This suggests that p53 may contribute to survival factor dependence. To assess the role of wild‐type p53 in mediating apoptosis following survival factor withdrawal, we interfered with endogenous p53 activity in interleukin‐3 (IL‐3)‐dependent cells. Extended survival without IL‐3 was conferred by recombinant retroviruses encoding either a full‐length p53 mutant or a C‐terminal p53 miniprotein, both of which can act as negative‐dominant inhibitors of wild‐type p53. On the other hand, excess wild‐type p53 activity failed to elicit apoptosis as long as IL‐3 was present. We propose that p53 is a positive, though not exclusive, mediator of survival factor dependence in hematopoietic cells.

The role of p53 in death of IL-3-dependent cells in response to cytotoxic drugs

“…Table 3 shows that apoptosis of Bip-2 cells was delayed under these conditions compared to that of Baf-3 cells. A delay in apoptosis following IL-3 removal has also been described when the function of p53 is inhibited by a dominant interfering mutant (Gottlieb et al, 1994). We also examined the rate of entry into apoptosis of Baf-3 and Bip-2 cells in the presence of IL-3 and lethal concentration of methotrexate and FUdR.…”

Involvement of p53 and Raf/MEK/ERK pathways in hematopoietic drug resistance

“…33,34 Infection of cells with retroviral vectors FL5.12 and FL/Doxo cells were infected with retroviral vectors encoding WT or DN p53, constitutively active (CA) (DStuI-MEK-LIDEMANE) or DN MEK1 (MEKLIDA) or an empty retroviral vector (pLXSN), as previously described. [36][37][38] Stably infected (WT and DN p53-and pLXSN-transduced) cells were selected with IL-3 þ 2 mg ml À1 G418 (Geneticin, Invitrogen). 34 Stably infected (DN and CA MEK1, BRAF(WT):ER* and BRAF(V600E): ER*) cells were selected with IL-3 þ 2 mg ml À1 puromycin (Sigma-Aldrich).…”

Activation and activities of the p53 tumour suppressor protein

“…Loss of survival signalling can augment p53-mediated apoptosis (Gottlieb et al, 1994;Abrahamson et al, 1995;Canman et al, 1995;Lin and Benchimol, 1995;Prisco et al, 1997), and the ability of p53 to negatively regulate the IGF pathway (Buckbinder et al, 1995) and inhibit intergrin-associated survival signalling may further sensitize cells to p53-induced death (Bachelder et al, 1999). The NF-κB transcription factor has lately been shown to play an important role in p53-mediated apoptosis (Ryan et al, 2000), in contrast to the anti-apoptotic effect of NF-κB induced in response to TNF (Van Antwerp et al, 1996;Phillips et al, 1999).…”