Cytokines inhibit p53-mediated apoptosis but not p53-mediated G1 arrest.

AUTOR(ES)

Lin, Y

RESUMO

Murine erythroleukemia cells that lack endogenous p53 expression were transfected with a temperature-sensitive p53 allele. The temperature-sensitive p53 protein behaves as a mutant polypeptide at 37 degrees C and as a wild-type polypeptide at 32 degrees C. Three independent clones expressing the temperature-sensitive p53 protein were characterized with respect to p53-mediated G1 cell cycle arrest, apoptosis, and differentiation. Clone ts5.203 responded to p53 activation at 32 degrees C by undergoing G1 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 G1. 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 G1 arrest. These observations indicate that apoptosis and G1 arrest can be effectively uncoupled through the action of cytokines acting as survival factors and are consistent with the idea that apoptosis and G1 arrest represent separate functions of p53. Clones ts15.15 and tsCB3.4 responded to p53 activation at 32 degrees C by undergoing G1 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.

Documentos Relacionados

• Chk2 is dispensable for p53-mediated G1 arrest but is required for a latent p53-mediated apoptotic response
• Constitutive expression of B-myb can bypass p53-induced Waf1/Cip1-mediated G1 arrest.
• Enhanced binding of a 95 kDa protein to p53 in cells undergoing p53-mediated growth arrest.
• Sensitivity and selectivity of the DNA damage sensor responsible for activating p53-dependent G1 arrest.
• Wild-type but not Alzheimer-mutant amyloid precursor protein confers resistance against p53-mediated apoptosis