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Growth-condition-dependent regulation of insulin-like growth factor II mRNA stability.

ABSTRACT: Insulin-like growth factor II (IGF-II) is synthesized in many tissues, but the main site of production is the liver. In this paper we show that IGF-II mRNA levels are dependent on the growth conditions of the cells. In Hep3B cells, serum deprivation leads to a marked increase in IGF-II mRNA levels. Serum stimulation of starved Hep3B cells induces a decrease in the amount of IGF-II mRNA, which is not caused by a change in promoter activity. IGF-II mRNAs are subject to endonucleolytic cleavage, a process that requires two widely separated elements in the 3' untranslated region of the mRNA. Specific regions of these elements can form a stable stem structure which is involved in the formation of RNA-protein complexes. By employing electrophoretic mobility shift assays, two complexes have been identified in cytoplasmic extracts of Hep3B cells. The formation of these complexes is related to the growth conditions of the cells and is correlated with the regulation of IGF-II mRNA levels. Our data suggest that, depending on whether serum is present or absent, a transition from one complex to the other occurs. A decrease in the IGF-II mRNA level is also observed when IGF-I or IGF-II is added to serum-deprived Hep3B cells, possibly providing a feedback mechanism for IGF-II production. The serum-induced degradation of IGF-II mRNAs does not require de novo protein synthesis, and is abolished by rapamycin, an inhibitor of p70 S6 kinase.

SUBMITTER: Scheper W

PROVIDER: S-EPMC1217607 | biostudies-other | 1996 Aug

REPOSITORIES: biostudies-other

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Project description:CRC cells evolve a variety of strategies to limit or circumvent apoptosis cell death. RNA binding proteins (RBPs) regulate many of the molecular mechanisms that underlie the development of cancer. The insulin-like growth factor II mRNA-binding proteins (IMP) family are oncofoetal RBPs, consisting of IMP1, IMP2 and IMP3, which have an important role in RNA metabolism. IMP3 is highly expressed in colorectal cancer (CRC) tissue, where its expression often correlates with poor prognosis. However, the role of IMP3 in CRC is not fully understood. IMP3 expression was analysed using a public database and by Western blotting and immunohistochemistry in human colon samples derived from patients with sporadic CRC and healthy subjects. To address whether IMP3 controls cancer cell survival, we analysed cell death pathways in in vitro and in vivo experiments after IMP3 downregulation by siRNA or an antisense oligonucleotide. IMP3 was highly expressed in CRC samples compared to normal control tissues. The knockdown of IMP3 enhanced a caspase-independent cell death in CRC cell lines. Furthermore, the treatment of CRC cells with IMP3 siRNA did not alter the expression of GSDMD, GPX-4 and the activated form of RIP3, three key molecules that govern pyroptosis, ferroptosis and necroptosis, respectively. Abrogation of IMP3 in CRC significantly reduced Bcl-2 and Bcl-xL mRNA and was associated with an altered mitochondrial membrane potential that allowed the nuclear migration of the apoptosis-inducing factor (AIF). Moreover, specific immunoprecipitation experiments on CRC human cell lines indicated that IMP3 binds Bcl-2 and Bcl-xL mRNA, suggesting that IMP3 acts as a regulator of the intrinsic apoptotic pathway through the surveillance of anti-apoptotic Bcl mRNA metabolism. Finally, we showed that IMP3 block inhibited the growth of CRC cell lines in vivo after transplantation into immunodeficient mice. Altogether, these data support a novel role for IMP3 in controlling the intrinsic caspase-independent apoptotic pathway in CRC.

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Growth-condition-dependent regulation of insulin-like growth factor II mRNA stability.

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