TP53INP1 is a novel p73 target gene that induces cell cycle arrest and cell death by modulating p73 transcriptional activity.
TP53INP1 is an alternatively spliced gene encoding two nuclear protein isoforms (TP53INP1alpha and TP53INP1beta), whose transcription is activated by p53. When overexpressed, both isoforms induce cell cycle arrest in G1 and enhance p53-mediated apoptosis. TP53INP1s also interact with the p53 gene and regulate p53 transcriptional activity. We report here that TP53INP1 expression is induced during experimental acute pancreatitis in p53-/- mice and in cisplatin-treated p53-/- mouse embryo fibroblasts (MEFs). We demonstrate that ectopic expression of p73, a p53 homologue, leads to TP53INP1 induction in p53-deficient cells. In turn, TP53INP1s alters the transactivation capacity of p73 on several p53-target genes, including TP53INP1 itself, demonstrating a functional association between p73 and TP53INP1s. Also, when overexpressed in p53-deficient cells, TP53INP1s inhibit cell growth and promote cell death as assessed by cell cycle analysis and colony formation assays. Finally, we show that TP53INP1s potentiate the capacity of p73 to inhibit cell growth, that effect being prevented when the p53 mutant R175H is expressed or when p73 expression is blocked by a siRNA. These results suggest that TP53INP1s are functionally associated with p73 to regulate cell cycle progression and apoptosis, independently from p53.
Tomasini
Richard
R
INSERM U624, Stress Cellulaire, IFR 137-Institut de Cancérologie et Immunologie de Marseille, Université de la Méditerranée, Marseille, France.
Seux
Mylène
M
Nowak
Jonathan
J
Bontemps
Caroline
C
Carrier
Alice
A
Dagorn
Jean-Charles
JC
Pébusque
Marie-Josèphe
MJ
Iovanna
Juan L
JL
Dusetti
Nelson J
NJ
D000208:Acute Disease; D017398:Alternative Splicing; D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D002453:Cell Cycle / Q000502:physiology*; D016923:Cell Death / Q000502:physiology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D006360:Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics*; D010195:Pancreatitis / Q000235:genetics; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics; D025521:Tumor Suppressor Proteins
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D009687:Nuclear Proteins; C429767:TP53INP1 protein, human; C000606460:TP73 protein, human; C498965:Trp53inp1 protein, mouse; C000606368:Trp73 protein, mouse; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D002945:Cisplatin