Abstract
Growing evidence suggests the Δ133p53α isoform may function as an oncogene. It is overexpressed in many tumors, stimulates pathways involved in tumor progression, and inhibits some activities of wild-type p53, including transactivation and apoptosis. We hypothesized that Δ133p53α would have an even more profound effect on p53 variants with weaker tumor-suppressor capability. We tested this using a mouse model heterozygous for a Δ133p53α-like isoform (Δ122p53) and a p53 mutant with weak tumor-suppressor function (mΔpro). The Δ122p53/mΔpro mice showed a unique survival curve with a wide range of survival times (92–495 days) which was much greater than mΔpro/- mice (range 120–250 days) and mice heterozygous for the Δ122p53 and p53 null alleles (Δ122p53/-, range 78–150 days), suggesting Δ122p53 increased the tumor-suppressor activity of mΔpro. Moreover, some of the mice that survived longest only developed benign tumors. In vitro analyses to investigate why some Δ122p53/mΔpro mice were protected from aggressive tumors revealed that Δ122p53 stabilized mΔpro and prolonged the response to DNA damage. Similar effects of Δ122p53 and Δ133p53α were observed on wild-type of full-length p53, but these did not result in improved biological responses. The data suggest that Δ122p53 (and Δ133p53α) could offer some protection against tumors by enhancing the p53 response to stress.
Highlights
The Δ133p53α isoform is expressed in many tissues, but elevated levels have been found in several cancers.[11,15,16]
Using a mouse model of the Δ133p53α isoform (Δ122p53), we previously showed that the isoform had powerful tumorigenic and inflammatory functions, and in heterozygous mice, could partially inhibit the tumor-suppressor activities of wild-type p53.19 In this paper, we report that Δ122p53 enhanced the tumor-suppressor activities of the attenuated p53 mutant mΔpro
This was shown by the observation that Δ122p53/ mΔpro mice survived much longer than mΔpro/- and Δ122p53/- mice and were largely protected from the aggressive early onset T-cell lymphomas typical of p53 − / − mice, and the least differentiated Diffuse large B-cell lymphoma (DLCL) and DLCL-like tumors common in Δ122p53/- mice
Summary
The Δ133p53α isoform is expressed in many tissues, but elevated levels have been found in several cancers.[11,15,16]. The function(s) of Δ133p53α are not fully understood, growing evidence suggests it may have tumor-promoting capacities. Reducing Δ133p53α levels in the U87MG glioblastoma cell line reduced its ability to migrate and stimulate angiogenesis.[17] Δ133p53α may interfere with the tumor-suppressor functions of FLp53. We reasoned that in an environment where p53 tumor-suppression capacity is compromised, such as in the context of the R72P allele[22,23,24] or where p53 levels are reduced,[25,26,27] the influence of Δ133p53α isoform on FLp53 function would be greater, leading to rapid tumor formation with a phenotype that would resemble that of the isoform alone. We generated mice heterozygous for Received 28.12.14; revised 09.4.15; accepted 06.5.15; Edited by M Agostini
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