Abstract
p53 is an important tumor suppressor and stress response mediator. Proper control of p53 level and activity is tightly associated with its function. Posttranslational modifications and the interactions with Mdm2 and Mdm4 are major mechanisms controlling p53 activity and stability. As p53 protein is short-lived and hardly detectable in unstressed situations, less is known on its basal level expression and the corresponding controlling mechanisms in vivo. In addition, it also remains obscure how p53 expression might contribute to its functional regulation. In this study, we established bacterial artificial chromosome transgenic E.coli β-galactosidase Z gene reporter mice to monitor p53 expression in mouse tissues and identify important regulatory elements critical for the expression in vivo. We revealed preferentially high level of p53 reporter expressions in the proliferating, but not the differentiated compartments of the majority of tissues during development and tissue homeostasis. In addition, tumors as well as regenerating tissues in the p53 reporter mice also expressed high level of β-gal. Furthermore, both the enhancer box sequence (CANNTG) in the p53 promoter and the 3′ terminal untranslated region element were critical in mediating the high-level expression of the reporter. We also provided evidence that cellular myelocytomatosis oncogene was a critical player regulating p53 mRNA expression in proliferating cells and tissues. Finally, we found robust p53 activation preferentially in the proliferating compartment of mouse tissues upon DNA damage and the proliferating cells exhibited an enhanced p53 response as compared with cells in a quiescent state. Together, these results suggested a highly regulated expression pattern of p53 in the proliferating compartment controlled by both transcriptional and posttranscriptional mechanisms, and such regulated p53 expression may impose functional significance upon stress by setting up a precautionary mode in defense of cellular transformation and tumorigenesis.
Highlights
Repression of these two inhibitors by stress stimuli is the major posttranslational regulatory mechanism controlling p53 activity and stability.[3]
Cell Death and Disease was at high levels in the hair follicle and basal layer of the skin, external granular layer (EGL) of the cerebellum and intestinal crypts (Figure 1a), which are actively proliferating; in contrast, p53 mRNAs were at much lower levels in supra basal layer of the skin, internal granular layer (IGL) of the cerebellum and villus of the small intestine (Figure 1a), which belong to the differentiated compartments
To assess the importance of p53 3ʹ terminal untranslated region (3ʹUTR) in the regulation of basal p53 expression, we established p53PZS(or PZS) bacterial artificial chromosome (BAC) transgenic mice in which the inserted E.coli β-galactosidase Z gene (LacZ) reporter gene was followed only by the simian vacuolating virus 40 polyadenylation sequences (SV40pA) to monitor the expression of p53 without its own 3ʹUTR sequence (Figure 1b)
Summary
Repression of these two inhibitors by stress stimuli is the major posttranslational regulatory mechanism controlling p53 activity and stability.[3]. Apoptosis increased with p53 levels in cultured cells.[4] In mice, additional 1–2 copies of wild type p53 did not impact mouse development, growth and senescence, but significantly enhanced the sensitivity to γ-irradiation and strengthened the resistance to tumorigenesis.[5] On the other hand, p53 haploinsufficiency was observed in a variety of situations including tumorigenesis and stress responses. Both individuals harboring a p53 germline mutation in the Li–Fraumeni families and p53 heterozygous mice exhibited increased incidence of tumors, some of which apparently did not lose the wild-type allele. More works are needed to decipher or distinguish the underlying mechanisms influencing the p53 regulatory disparities
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