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Blood, Vol. 92 No. 3 (August 1), 1998:
pp. 1003-1010
Distinct Apoptotic Responses Imparted by c-myc and max
Chadd E. Nesbit,
Saijun Fan,
Hong Zhang, and
Edward V. Prochownik
From the Section of Hematology/Oncology, the Department of
Pediatrics, Children's Hospital of Pittsburgh; the Department of
Molecular Genetics and Biochemistry, the University of Pittsburgh
Medical Center; and the University of Pittsburgh Cancer Institute,
Pittsburgh, PA.
The c-myc oncoprotein accelerates programmed cell death (apoptosis)
after growth factor deprivation or pharmacological insult in many cell
lines. We have shown that max, the obligate c-myc heterodimeric partner
protein, also promotes apoptosis after serum withdrawal in NIH3T3
fibroblasts or cytokine deprivation in interleukin-3 (IL-3)-dependent
32D murine myeloid cells. We now show that c-myc- and
max-overexpressing 32D cells differ in the nature of their apoptotic
responses after IL-3 removal or treatment with chemotherapeutic compounds. In the presence of IL-3, c-myc overexpression enhances the
sensitivity of 32D cells to Etoposide (Sigma, St Louis, MO), Adriamycin
(Pharmacia, Columbus, OH), and Camptothecin (Sigma), whereas max
overexpression increases sensitivity only to Camptothecin. Drug
treatment of c-myc-overexpressing cells in the absence of IL-3 did not
alter the spectrum of drug sensitivity other than to additively
accelerate cell death. In contrast, enhanced sensitivity to Adriamycin,
Etoposide, and Taxol (Bristol-Meyers Squibb, Princeton, NJ) was
revealed in max-overexpressing cells concurrently deprived of IL-3.
Differential rates of apoptosis were not strictly correlated with the
ability of the drugs to promote G1 or G2/M arrest. Ectopic expression
of Bcl-2 or Bcl-XL blocked drug-induced apoptosis in both
cell lines. In contrast, whereas Bcl-2 blocked apoptosis in both cell
lines in response to IL-3 withdrawal, Bcl-XL blocked apoptosis in max-overexpressing cells but not in c-myc-overexpressing cells. These results provide mechanistic underpinnings for the idea
that c-myc and max modulate distinct apoptotic pathways.
© 1998 by The American Society of Hematology.
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