Document Detail


HIF-1 or HIF-2 induction is sufficient to achieve cell cycle arrest in NIH3T3 mouse fibroblasts independent from hypoxia.
MedLine Citation:
PMID:  19342889     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Hypoxia is a severe stress which induces physiological and molecular adaptations, where the latter is dominated by the Hypoxia-inducible transcription Factor (HIF). A well described response on cellular level upon exposure to hypoxia is a reversible cell cycle arrest, which probably renders the cells more resistant to the difficult environment. The individual roles of hypoxia itself and of the isoforms HIF-1alpha and HIF-2alpha in cell cycle regulation are poorly understood and discussed controversially. In order to characterize the isolated effect of both HIFalpha isoforms on the cell cycle we generated tetracycline inducible, HIF-1alpha and -2alpha expressing NIH3T3 cells. The cDNAs for HIFalpha were mutated to generate stable and active HIF under normoxia. Upon activation of both HIFalpha subunits, the total number of living cells was reduced and long-term stimulation of HIF led to complete loss of transgene expression, implicating a strong negative selection pressure. Equally, colony forming activity was reduced by activation of both HIFalpha subunits. Cell cycle analyses showed that HIF activation resulted in a prominent cell cycle arrest in G(1)-phase, similarly to the hypoxic effect. Both, HIF-1alpha and HIF-2alpha were able to induce the expression of the cyclin-dependent kinase inhibitor p27 on reporter gene and protein level. Our study shows that HIF-1 and HIF-2 can individually arrest the cell cycle independent from hypoxia. These findings have implications for the resistance of tumor cells to the environment and treatment, but also for physiological cells. Importantly, recent approaches to stabilize HIFalpha in normoxia could have deleterious effects on proliferating tissues.
Authors:
Thomas Hackenbeck; Karl Xaver Knaup; Ruth Schietke; Johannes Schödel; Carsten Willam; Xiaoqing Wu; Christina Warnecke; Kai-Uwe Eckardt; Michael Sean Wiesener
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-05-27
Journal Detail:
Title:  Cell cycle (Georgetown, Tex.)     Volume:  8     ISSN:  1551-4005     ISO Abbreviation:  Cell Cycle     Publication Date:  2009 May 
Date Detail:
Created Date:  2009-04-22     Completed Date:  2009-06-03     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101137841     Medline TA:  Cell Cycle     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1386-95     Citation Subset:  IM    
Affiliation:
Interdisciplinary Centre for Clinical Research (IZKF), University of Erlangen-Nuremberg, Erlangen, Germany.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis
Basic Helix-Loop-Helix Transcription Factors / metabolism*
Cell Cycle*
Cell Hypoxia
Cell Proliferation
Clone Cells
Cyclin-Dependent Kinase Inhibitor p27 / metabolism
Fibroblasts / cytology*,  metabolism*
G1 Phase
Genes, Reporter
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
Mice
NIH 3T3 Cells
Protein Subunits / metabolism
Transgenes
Chemical
Reg. No./Substance:
0/Basic Helix-Loop-Helix Transcription Factors; 0/Hif1a protein, mouse; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/Protein Subunits; 0/endothelial PAS domain-containing protein 1; 147604-94-2/Cyclin-Dependent Kinase Inhibitor p27

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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