Repression of the antiapoptotic molecule galectin-3 by homeodomain-interacting protein kinase 2-activated p53 is required for p53-induced apoptosis.
Galectin 3 (Gal-3), a member of the beta-galactoside binding lectin family, exhibits antiapoptotic functions, and its aberrant expression is involved in various aspects of tumor progression. Here we show that p53-induced apoptosis is associated with transcriptional repression of Gal-3. Previously, it has been reported that phosphorylation of p53 at Ser46 is important for transcription of proapoptotic genes and induction of apoptosis and that homeodomain-interacting protein kinase 2 (HIPK2) is specifically involved in these functions. We show that HIPK2 cooperates with p53 in Gal-3 repression and that this cooperation requires HIPK2 kinase activity. Gene-specific RNA interference demonstrates that HIPK2 is essential for repression of Gal-3 upon induction of p53-dependent apoptosis. Furthermore, expression of a nonrepressible Gal-3 prevents HIPK2- and p53-induced apoptosis. These results reveal a new apoptotic pathway induced by HIPK2-activated p53 and requiring repression of the antiapoptotic factor Gal-3.
Cecchinelli
Barbara
B
Department of Experimental Oncology, Regina Elena Cancer Institute, 00158 Rome, Italy.
Lavra
Luca
L
Rinaldo
Cinzia
C
Iacovelli
Stefano
S
Gurtner
Aymone
A
Gasbarri
Alessandra
A
Ulivieri
Alessandra
A
Del Prete
Fabrizio
F
Trovato
Maria
M
Piaggio
Giulia
G
Bartolazzi
Armando
A
Soddu
Silvia
S
Sciacchitano
Salvatore
S
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D018076:DNA, Complementary / Q000235:genetics; D037502:Galectin 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D037161:Galectins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012694:Serine / Q000737:chemistry; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
D002352:Carrier Proteins; D018076:DNA, Complementary; D037502:Galectin 3; D037161:Galectins; C485095:Lgals3 protein, mouse; D009687:Nuclear Proteins; D011994:Recombinant Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D012694:Serine; C115114:HIPK2 protein, human; D017346:Protein Serine-Threonine Kinases