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Department of Pharmacology, University of Pittsburgh and
Experimental Therapeutics Program, University of Pittsburgh Cancer
Institute, Pittsburgh, Pennsylvania 15261
Metallothioneins (MTs) are major intracellular, zinc-binding proteins
with antioxidant properties. Mouse embryonic cells null for MT due to
loss of functional MT I and II genes (MT
/) were more susceptible to
apoptotic death after exposure to tert-butyl hydroperoxide or the anti-cancer agents cytosine arabinoside, bleomycin, melphalan, and
cis-dichlorodiammineplatinum(II) compared with wild-type
mouse embryonic cells (MT+/+). We measured basal levels of the tumor
suppressor protein p53 and the death effector protein Bax and found the
basal levels of both proteins were higher in MT null cells compared
with MT+/+ cells. After treatment with the DNA-damaging agent
cis-dichlorodiammineplatinum(II), p53 protein levels
were induced in both MT+/+ and MT/ cells with MT null cells always
maintaining the highest p53 levels. The elevated sensitivity to
apoptosis was not restricted to embryonic cells. Primary pulmonary
fibroblasts were isolated from distinct litters of MT null,
heterozygous, and wild-type mice, and all had undetectable basal MT
levels. Zinc exposure increased MT levels in the wild-type and
heterozygous fibroblasts but not in the MT null fibroblasts. Consistent
with the induced MT levels, we found MT+/+ and MT+/ embryonic cells
were less sensitive to
cis-dichlorodiammineplatinum(II)-induced apoptosis
compared with MT/ cells. Our results implicate MT as a
stress-responsive factor that can regulate apoptotic engagement.
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