Transgenic mice with p53-responsive lacZ: p53 activity varies dramatically during normal development and determines radiation and drug sensitivity in vivo.
To analyze the involvement of p53-dependent transcriptional activation in normal development and in response to DNA damage in vivo, we created transgenic mice with a lacZ reporter gene under the control of a p53-responsive promoter. Five independent strains showed similar patterns of transgene expression. In untreated animals, lacZ expression was limited to the developing nervous system of embryos and newborn mice and was strongly decreased in the adult brain. gamma-irradiation or adriamycin treatment induced lacZ expression in the majority of cells of early embryos and in the spleen, thymus and small intestine in adult mice. Transgene expression was p53 dependent and coincided with the sites of strong p53 accumulation. The lacZ-expressing tissues and early embryos, unlike other adult tissues and late embryos, are characterized by high levels of p53 mRNA expression and respond to DNA damage by massive apoptotic cell death. Analysis of p53-null mice showed that this apoptosis is p53 dependent. These data suggest that p53 activity, monitored by the reporter lacZ transgene, is the determinant of radiation and drug sensitivity in vivo and indicate the importance of tissue and stage specificity of p53 regulation at the level of mRNA expression.
Komarova
E A
EA
Department of Genetics, University of Illinois at Chicago, 60607, USA.
Chernov
M V
MV
Franks
R
R
Wang
K
K
Armin
G
G
Zelnick
C R
CR
Chin
D M
DM
Bacus
S S
SS
Stark
G R
GR
Gudkov
A V
AV
D016475:3T3 Cells; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D001483:Base Sequence; D004249:DNA Damage; D017931:DNA Primers / Q000235:genetics; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000528:radiation effects; D017930:Genes, Reporter; D016158:Genes, p53; D007763:Lac Operon; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011836:Radiation Tolerance / Q000235:genetics; D014018:Tissue Distribution; D015533:Transcriptional Activation / Q000187:drug effects / Q000528:radiation effects; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*
D017931:DNA Primers; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin