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PMID: 19214186 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

A GLI1-p53 inhibitory loop controls neural stem cell and tumour cell numbers.

The EMBO journal ·Vol. 28 ·No. 6 ·2009-03-18 ·Pages 663-76

Stecca B, Ruiz i Altaba A

Abstract

How cell numbers are determined is not understood. Hedgehog-Gli activity is involved in precursor cell proliferation and stem cell self-renewal, and its deregulation sustains the growth of many human tumours. However, it is not known whether GLI1, the final mediator of Hh signals, controls stem cell numbers, and how its activity is restricted to curtail tumourigenesis. Here we have altered the levels of GLI1 and p53, the major tumour suppressor, in multiple systems. We show that GLI1 expression in Nestin+ neural progenitors increases precursor and clonogenic stem cell numbers in vivo and in vitro. In contrast, p53 inhibits GLI1-driven neural stem cell self-renewal, tumour growth and proliferation. Mechanistically, p53 inhibits the activity, nuclear localisation and levels of GLI1 and in turn, GLI1 represses p53, establishing an inhibitory loop. We also find that p53 regulates the phosphorylation of a novel N' truncated putative activator isoform of GLI1 in human cells. The balance of GLI1 and p53 functions, thus, determines cell numbers, and prevalence of p53 restricts GLI1-driven stem cell expansion and tumourigenesis.

MeSH Terms
Animals Brain/metabolism,pathology Cell Count Cell Nucleus/metabolism Cell Proliferation Colony-Forming Units Assay Embryonic Stem Cells/cytology,metabolism Epidermis/metabolism,pathology Hedgehog Proteins/metabolism Humans Hyperplasia Kruppel-Like Transcription Factors/metabolism Mice Neoplasms/metabolism,pathology Neurons/cytology,metabolism Organ Size Protein Isoforms/metabolism Protein Transport Repressor Proteins/metabolism Signal Transduction Stem Cells/cytology,metabolism Transcription Factors/metabolism Tumor Suppressor Protein p53/metabolism Up-Regulation Zinc Finger Protein GLI1
Chemicals
GLI1 protein, human Gli1 protein, mouse Hedgehog Proteins Kruppel-Like Transcription Factors Protein Isoforms Repressor Proteins Shh protein, mouse Transcription Factors Tumor Suppressor Protein p53 Zinc Finger Protein GLI1
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Stecca Barbara
Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
Ruiz i Altaba Ariel
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
1460-2075
DOI
10.1038/emboj.2009.16
Published
2009-03-18
Epub
2009-00-12
Pages
663-76
Language
English
Region
England
NLM ID
8208664
PMCID
PMC2647769
Subset
IM
External Links
PubMed source DOI: 10.1038/emboj.2009.16 PMC Full Text View journal details
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