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Novel functions of chromatin-bound IκBα in oncogenic transformation.

ABSTRACT: The nuclear factor-κB (NF-κB) signalling pathway participates in a multitude of biological processes, which imply the requirement of a complex and precise regulation. IκB (for Inhibitor of kappaB) proteins, which bind and retain NF-κB dimers in the cytoplasm, are the main contributors to negative regulation of NF-κB under non-stimulation conditions. Nevertheless, increasing evidences indicate that IκB proteins exert specific nuclear roles that directly contribute to the control of gene transcription. In particular, hypophosphorylated IκBβ can bind the promoter region of TNFα leading to persistent gene transcription in macrophages and contributing to the regulation of the inflammatory response. Recently, we demonstrated that phosphorylated and SUMOylated IκBα reside in the nucleus of the cells where it binds to chromatin leading to specific transcriptional repression. Mechanistically, IκBα associates and regulates Polycomb Repressor Complex activity, a function that is evolutionary conserved from flies to mammals, as indicate the homeotic phenotype of Drosophila mutants. Here we discuss the implications of chromatin-bound IκBα function in the context of tumorigenesis.

SUBMITTER: Espinosa L

PROVIDER: S-EPMC4453743 | biostudies-other | 2014 Oct

REPOSITORIES: biostudies-other

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Project description:BackgroundIn around 50% of all human cancers the tumor suppressor p53 is mutated. It is generally assumed that in the remaining tumors the wild-type p53 protein is functionally impaired. The two main inhibitors of p53, hMDM2 (MDM2) and hMDMX (MDMX/MDM4) are frequently overexpressed in wild-type p53 tumors. Whereas the main activity of hMDM2 is to degrade p53 protein, its close homolog hMDMX does not degrade p53, but it represses its transcriptional activity. Here we study the role of hMDMX in the neoplastic transformation of human fibroblasts and embryonic retinoblasts, since a high number of retinoblastomas contain elevated hMDMX levels.MethodsWe made use of an in vitro transformation model using a retroviral system of RNA interference and gene overexpression in primary human fibroblasts and embryonic retinoblasts. Consecutive knockdown of RB and p53, overexpression of SV40-small t, oncogenic HRasV12 and HA-hMDMX resulted in a number of stable cell lines representing different stages of the transformation process, enabling a comparison between loss of p53 and hMDMX overexpression. The cell lines were tested in various assays to assess their oncogenic potential.ResultsBoth p53-knockdown and hMDMX overexpression accelerated proliferation and prevented growth suppression induced by introduction of oncogenic Ras, which was required for anchorage-independent growth and the ability to form tumors in vivo. Furthermore, we found that hMDMX overexpression represses basal p53 activity to some extent. Transformed fibroblasts with very high levels of hMDMX became largely resistant to the p53 reactivating drug Nutlin-3. The Nutlin-3 response of hMDMX transformed retinoblasts was intact and resembled that of retinoblastoma cell lines.ConclusionsOur studies show that hMDMX has the essential properties of an oncogene. Its constitutive expression contributes to the oncogenic phenotype of transformed human cells. Its main function appears to be p53 inactivation. Therefore, developing new drugs targeting hMDMX is a valid approach to obtain new treatments for a subset of human tumors expressing wild-type p53.

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Novel functions of chromatin-bound IκBα in oncogenic transformation.

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