Colitis and Colitis-Associated Cancer Are Exacerbated in Mice Deficient for Tumor Protein 53-Induced Nuclear Protein 1

Abstract

Tumor protein 53-induced nuclear protein 1 (TP53INP1) is an antiproliferative and proapoptotic protein involved in cell stress response. To address its physiological roles in colorectal cancer and colitis, we generated and tested the susceptibility of Trp53inp1-deficient mice to the development of colorectal tumors induced by injection of the carcinogen azoxymethane followed by dextran sulfate sodium (DSS)-induced chronic colitis. Trp53inp1-deficient mice showed an increased incidence and multiplicity of tumors compared to those of wild-type (WT) mice. Furthermore, acute colitis induced by DSS treatment was more severe in Trp53inp1-deficient mice than in WT mice. Treatment with the antioxidant N-acetylcysteine prevented colitis and colitisassociated tumorigenesis more efficiently in WT mice than in Trp53inp1-deficient mice, suggesting a higher oxidative load in the latter. Consistently, we demonstrated by electron spin resonance and spin trapping that colons derived from deficient mice produced more free radicals than those of the WT during colitis and that the basal blood level of the antioxidant ascorbate was decreased in Trp53inp1-deficient mice. Collectively, these results indicate that the oxidative load is higher in Trp53inp1-deficient mice than in WT mice, generating a more-severe DSS-induced colitis, which favors development of colorectal tumors in Trp53inp1-deficient mice.

Eμ/miR-125b transgenic mice develop lethal B-cell malignancies

“…Indeed, Trp53inp1 null mice were shown to be susceptible to cancer development. 31 Of clinical relevance, we found that miR-125b was overexpressed in various hematopoietic diseases including BCP-ALL, AML and myelodysplastic syndrome without chromosomal translocations, t(11;14)(q24;q32) or t(2;11)(p21;q23). Mature miR-125b is also produced from miR-125b-2 mapped on 21q21.…”

“…Trp53inp1 is a pro-apoptotic gene induced by cell stress, [16][17][18][19] and its repression is involved in tumorigenesis. 30,31 To confirm that Trp53inp1 is a direct target gene of miR-125b, the wild-type 3 0 UTR of Trp53inp1 or the mutated 3 0 UTR was cloned to downstream of the Renilla luciferase open reading frame (Figure 3a). We performed luciferase assays and found that miR-125b directly represses the expression of the reporter gene with the Trp53inp1-3 0 UTR but not that with mutated 3 0 UTR of Trp53inp1 (Figure 3a).…”

TP53INP1 decreases pancreatic cancer cell migration by regulating SPARC expression

“…Cutaneous wound closure TP53INP1 wild-type or deficient mice were as described in Gommeaux et al, 2007. In this work, C57BL/6 mice backcrossed by nine generations were used.…”

TP53INP1, a tumor suppressor, interacts with LC3 and ATG8-family proteins through the LC3-interacting region (LIR) and promotes autophagy-dependent cell death

“…7,8 Our laboratory demonstrated that TP53INP1 is a tumor suppressor on the basis of the following observations: (i) TP53INP1 deficient mice present with an increased susceptibility to tumor development; (ii) TP53INP1 is lost at very early stages of pancreatic carcinogenesis through a mechanism involving the oncogenic miR-155 microRNA and (iii) when TP53INP1 expression is restored in pancreatic cells, it suppresses xenograft growth by increasing apoptotic cell death through a caspase-dependent mechanism. 3,9,10 More recently, in an attempt to decipher the molecular mechanism by which TP53INP1 induces cell death, we found that it interacts with a family of proteins involved in autophagy. Such interaction had already been reported for the TP53INP1 paralog TP53INP2 (also known as DOR) that shows 30% of amino-acid identity with TP53INP1.…”