Genetic inactivation of the transcription factor TIF-IA leads to nucleolar disruption, cell cycle arrest, and p53-mediated apoptosis
Authors: Günter Schütz
Minqiang Chai
Ingrid Grummt
Emilio Casanova
Hermann-Josef Gröne
Yonggang Zhou
Eva Kiss
Xuejun Yuan
Journal: Molecular cell (2005)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: rRNA synthesis; TIF-IA; embryonic development; nucleoli; cell cycle arrest
Affiliations: Division of Molecular Biology of the Cell II, German Cancer Research Center, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.

Abstract:  Growth-dependent regulation of rRNA synthesis is mediated by TIF-IA, a basal transcription initiation factor for RNA polymerase I. We inactivated the murine TIF-IA gene by homologous recombination in mice and embryonic fibroblasts (MEFs). TIF-IA-/- embryos die before or at embryonic day 9.5 (E9.5), displaying retardation of growth and development. In MEFs, Cre-mediated depletion of TIF-IA leads to disruption of nucleoli, cell cycle arrest, upregulation of p53, and induction of apoptosis. Elevated levels of p53 after TIF-IA depletion are due to increased binding of ribosomal proteins, such as L11, to MDM2 and decreased interaction of MDM2 with p53 and p19(ARF). RNAi-induced loss of p53 overcomes proliferation arrest and apoptosis in response to TIF-IA ablation. The striking correlation between perturbation of nucleolar function, elevated levels of p53, and induction of cell suicide supports the view that the nucleolus is a stress sensor that regulates p53 activity. 

Retracted: No

PubPeer comments:
 This article was reviewed on the error bar podcast episode 3: https: theerrorbar.com ?e=3. The review was done in the light of newspaper headlines about the article. The slightly-edited transcript is copied here: headline: LONELY BRAINS LOOK DIFFERENT tweet: analysis of nearly forty thousand brain scans shows that adults who often feel lonely have structural and functional changes in parts of their brains sometimes associated with social interactions and mind-wandering description: Canada s Globe and Mail reports on a brain imaging study that looks at the structure and activity of thousands of brains stored in the UK s biobank database. within that database, nearly 40,000 people had several different kinds of brain scans of both the structure and the activity of the brain at rest. each of these people had also answered a simple question: do you often feel lonely? since the average age of participants was 55, this question taps into trait loneliness - people who have been feeling lonely for some time. these 40,000 brains were analysed using sophisticated computational and statistical methods. the researchers found that a set of brain regions known as the default network was strongly associated with people s response to that one question - do you often feel lonely? indeed, the amount of grey matter in this brain region was strongly associated with loneliness, as were the relationships between activity in this region and other regions. finally, some white matter pathways emerging from the hippocampus - which is an important part of the brain associated with memory - were also associated with loneliness evaluation: the authors of this study used sophisticated methods on the very large database of brain scans that they analysed. there was just a single question asked of the participants: do you often feel lonely, which they answered yes or no. and all of the complex data analysis was focussed on the relationship between that single answer and the brain. like most papers reviewed here, it is outside my specific expertise. however, this paper strikes me as a high quality bit of science. there are clear signs of goodness here: the research paper uses the word  uncertainty no fewer than six times - we love uncertainty at the error bar; it uses robust statistical methods that take account of the inherent biases in and limitations of the dataset. phrases like bootstrapping, Bonferroniu2019s correction, and Monte Carlo simulation in this paper really do make our hearts sing. this is quality science reporting both from the Globe and Mail, and from the scientists. we celebrate it. conclusion: a sophisticated, thorough and cautious analysis of a massive, high-quality dataset answers a very simple question: does feeling lonely change the brain? yes, it seems it does. ,