ID AND POL III

Regulation of RNA polymerase III transcription by Id proteins and E47

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 Obiettivo del progetto (Objective)

'The Id (Inhibitor of differentiation) family consists of four related transcription factors that are expressed at high levels in rapidly proliferating cells, including those found tumour cells. Overexpression of Id proteins in transgenic mice causes cancers. Ids have been shown to inhibit differentiation and promote cell proliferation in a variety of systems. This is achieved through interactions with other transcription factors such as MyoD, E47 and Ets. To date, all of the published targets of Id regulation are genes encoding protein. However we have discovered that Ids can also stimulate expression of short non-coding RNAs that are transcribed by RNA polymerase (pol) III, such as tRNA and 5S rRNA. This regulation appears to be direct, as endogenous Id proteins can be crosslinked in vivo to pol III transcribed genes. We also detect E47, a protein that promotes differentiation of several cell types, at these genes and find that it represses pol III transcription. This is consistent with the established antagonism between Id proteins and E47. It is well documented that pol III transcripts are overexpressed in many tumours. Our data suggests that, direct activation by Id proteins may contribute to this. It may be important, because elevated tRNA expression was recently shown to have proliferative and oncogenic effects in cell culture and in mice. This proposal aims to dissect molecular mechanisms responsible for Id mediated activation of tRNA and other pol III transcribed genes. We will also investigate the functional significance of pol III-Id interaction. RNAi will be used to test the hypothesis that Id proteins stimulate and E47 antagonises the proliferative and transforming effects of tRNA synthesis by pol III. Furthermore we will test if raising pol III transcription is required for the oncogenicity of an Id. Such experiments elucidate activity of Id proteins and their association with cancer.'

Introduzione (Teaser)

European researchers are investigating the role of one molecule that controls gene expression. Being able to control behaviour of this protein could translate into a potent therapy against cancer.

Descrizione progetto (Article)

Tumours are sites where many proteins are expressed in excess. This includes a family of four inhibitors of differentiation (Id) proteins. As transcription factors, all Id targets are genes and previous research has implicated these encoded proteins in cancer.

However, the 'Regulation of RNA polymerase III transcription by Id proteins and E47' (ID AND POL III) project has discovered that they can also stimulate expression of short non-coding RNAs that have transcription links with RNA polymerase III (pol III) genes. Pol III transcripts are often overexpressed in many tumours. A protein E47 represses poll III genes.

The researchers have established how Id2 and E47 are recruited at pol III genes and how they affect RNA pol III transcription. Moreover, they have also found out that E47 is necessary for Id2 recruitment at RNA pol III transcribed genes.

During the final part of the project, the scientists are going to investigate if pol III transcription is responsible for the transformation of normal cells into tumour cells. The researchers will look at the effects of moderating pol III transcription where Id proteins are involved.

Expected project results will elucidate more pathways that divert cells from the normal course of development to tumourigenesis. Such knowledge could lead to the development of targeted therapeutic interventions.