p53-dependent and p53-independent activation of apoptosis in mammary epithelial cells reveals a survival function of EGF and insulin.
The p53 tumor suppressor protein has been implicated as a mediator of programmed cell death (PCD). A series of nontransformed mammary epithelial cell (MEC) lines were used to correlate p53 function with activation of PCD. Treatment of MECs expressing mutant, inactive, or no p53 with DNA-damaging agents did not induce apoptosis. Upon introduction of temperature-sensitive p53 into HC11 cells, which lack wild-type (wt) p53, PCD was observed after mitomycin treatment at 32 degrees, when the ts p53 protein is in wt conformation. Thus, wt p53 mediates activation of PCD in response to mitomycin in HC11 cells. Treatment of the MCF10-A cells, which express wt p53, with various DNA-damaging agents led to nuclear accumulation of p53. Only mitomycin treatment led to an increase in the number of apoptotic nuclei. ErbB-2-transformed MCF10-A cells responded to mitomycin, cisplatin, and 5-Fl-uracil, suggesting that signaling from activated ErbB-2 enhances the cells ability to respond to DNA damage. A combination of high cell density and serum-free medium induces apoptosis in all MECs tested, irrespective of their p53 status. Under these conditions, EGF or insulin act as survival factors in preventing PCD. These data might elucidate some aspects of breast involution and tumorigenesis.
Merlo
G R
GR
Friedrich Miescher Institute, Basel, Switzerland.
Basolo
F
F
Fiore
L
L
Duboc
L
L
Hynes
N E
NE
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001940:Breast / Q000378:metabolism; D002452:Cell Count; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D004815:Epidermal Growth Factor / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D008321:Mammary Glands, Animal / Q000378:metabolism; D008937:Mitomycins / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014750:Vincristine / Q000494:pharmacology
D016895:Culture Media, Serum-Free; D007328:Insulin; D008937:Mitomycins; D016159:Tumor Suppressor Protein p53; D014750:Vincristine; D004815:Epidermal Growth Factor