Transgenic mice with p53-responsive lacZ: p53activity varies dramatically during normal development and determines radiation and drug sensitivity invivo

Abstract

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. γ‐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.

The Hippo pathway kinase Lats2 prevents DNA damage-induced apoptosis through inhibition of the tyrosine kinase c-Abl

“…38 Other studies have demonstrated differences in p53 accumulation and apoptosis depending on developmental state and cell type. [39][40][41][42] The general finding is that maximal induction of p53 is found in less-differentiated cells. 40 In a study that examined radiationinduced expression of p53 in the mouse intestine, 42 it was found that the highest p53 levels are at the base of the crypt in the small intestine in the stem cell population, with high levels also found in the proliferating transit cell population.…”

Mentha piperita as a pivotal neuro-protective agent against gamma irradiation induced DNA fragmentation and apoptosis

“…Gamma-irradiation induces apoptosis in many cell types depending upon the regulation of the signaling pathways of the tumor suppressor gene P53 (Clarke et al 1993;Komarova et al 1997) controlling cell proliferation and induction of apoptosis (White et al 1994;White 1995). c-irradiation induces DNA damage and triggers P53 activity up-regulation (Allday et al 1995;MacFarlane et al 1996;Loft and Poulsen 1996).…”

Mdm2: keeping p53 under control

“…These contrasting observations could possibly be reconciled by the recent proposal of an antiteratogenic function for p53 during development (Nicol et al, 1995;MacCallum et al, 1996;Hall and Lane, 1997). A restricted activation of the p53 protein was noticed after gamma irradiation of mouse embryos: indeed, tissues showing important proliferative activities at the time of the teratogenic insult may display the strongest response, including activation of the Mdm2 gene (MacCallum et al, 1996;Gottlieb et al, 1997;Komarova et al, 1997). An additional role for Mdm2 in development of vertebrate embryos remains to be demonstrated.…”