GADD153 CHOP, A DNA DAMAGE-INDUCIBLE PROTEIN, REDUCED CAAT/ENHANCER BINDING-PROTEIN ACTIVITIES AND INCREASED APOPTOSIS IN 32D CI3 MYELOID CELLS/

GADD153/CHOP is a DNA damage-inducible, nuclear Leucine zipper protein that is capable of producing a G(1)-S arrest in fibroblastic cells an d of dimerizing with and inhibiting CAAT/enhancer binding protein (C/E BP) activities. CHOP was induced in 32D cI3 myeloid cells exposed to m ethylmethane sulfonate (MMS), a DNA alkylating agent. The degree of in duction was dependent upon the dose of MMS to which the cells were exp osed. CHOP was not expressed, at least at similar levels, during 32D c I3 cell granulocytic differentiation or during their apoptosis upon gr owth factor withdrawal. High-level expression of exogenous CHOP in 32D cI3 cells markedly inhibited the trans-activation activities of endog enous C/EDPs. These cells proliferated in IL-3, although low-level ong oing apoptosis not observed with control cells was detected. When thes e cultures were transferred to granulocyte colony-stimulating factor ( G-CSF), the majority of the tells underwent apoptosis, although the le vels of CHOP did not increase. Similarly, 32D cI3 cells treated with d oses of MMS sufficient to induce endogenous CHOP underwent apoptosis m ore rapidly when placed in G-CSF-containing, compared with interleukin 3 (IL-3)-containing, medium, However, induction of CHOP by MMS was si milar in IL-3 and in G-CSF, The heightened sensitivity of 32D cI3 cell s to CHOP in G-CSF could result either from the loss of IL-3-specific signals or from increased expression of C/EDPs. Because myeloid leukem ias express C/EBP alpha, induction of CHOP might contribute to their c hemotherapy-induced apoptosis, and alterations in CHOP expression coul d contribute to their development of chemotherapy resistance.