Cytokines Inhibit p53-Mediated Apoptosis but Not p53-Mediated G₁ Arrest

Abstract

Murine erythroleukemia cells that lack endogenous p53 expression were transfected with a temperaturesensitive p53 allele. The temperature-sensitive p53 protein behaves as a mutant polypeptide at 37؇C and as a wild-type polypeptide at 32؇C. Three independent clones expressing the temperature-sensitive p53 protein were characterized with respect to p53-mediated G 1 cell cycle arrest, apoptosis, and differentiation. Clone ts5.203 responded to p53 activation at 32؇C by undergoing G 1 arrest, apoptosis, and differentiation. Apoptosis was seen in cells representative of all phases of the cell cycle and was not restricted to cells arrested in G 1 . The addition of a cytokine (erythropoietin, c-kit ligand, or interleukin-3) to the culture medium of ts5.203 cells blocked p53-mediated apoptosis and differentiation but not p53-mediated G 1 arrest. These observations indicate that apoptosis and G 1 arrest can be effectively uncoupled through the action of cytokines acting as survival factors and are consistent with the idea that apoptosis and G 1 arrest represent separate functions of p53. Clones ts15.15 and tsCB3.4 responded to p53 activation at 32؇C by undergoing G 1 arrest but not apoptosis. We demonstrate that tsCB3.4 secretes a factor with erythropoietin-like activity and that ts15.15 secretes a factor with interleukin-3 activity and suggest that autocrine secretion of these cytokines blocks p53-mediated apoptosis. These data provide a framework in which to understand the variable responses of cells to p53 overexpression.

PTEN Protects p53 from Mdm2 and Sensitizes Cancer Cells to Chemotherapy

“…The ability of p53 to induce death is antagonized by survival signaling, such as the PI3K/ Akt signaling pathway. p53-mediated apoptosis in erythroleukemia (54) and myeloid (55) cells is inhibited by interleukin-3, which delivers an anti-apoptotic signal through PI3K and Akt (39). In transformed baby rat kidney cells p53-mediated apoptosis is suppressed by oncogenic Ras, an activator of PI3K and Akt (56).…”

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).…”

Renewing the debate over the p53 apoptotic response

“…An alternative approach that has also been rewarding is based on the early observation by Oren and co-workers, 22 as well as others, 23,24 that certain cytokines can efficiently block p53-mediated Figure 1 Existing models for the p53 apoptotic pathway. (a) Low levels of p53 bind to high-affinity consensus sites within genes that negatively control cell cycle progression (e.g., p21 Cip1 and Gadd45a), whereas high levels of p53 are required to bind lower affinity sites in genes that trigger the apoptosis (e.g., Bax and Puma).…”

“…While cytokines do not disrupt p53-targeted gene transcription, they do interfere with p53-mediated cell death by upregulating key cell survival factors, such as Bcl-2 and Bcl-X L . [22][23][24][25][26] (e) p53 may associate with cofactors to induce synergistically proapoptotic genes. Two such cofactors, ASPP1 and ASPP2, enhance p53's ability to bind to the promoters of proapoptotic genes, but not cell cycle targets.…”