DeltaNp63 induces beta-catenin nuclear accumulation and signaling.
The P53 homolog p63 encodes multiple proteins with transactivating, apoptosis-inducing, and oncogenic activities. We showed that p63 is amplified and that DeltaNp63 isotypes are overexpressed in squamous cell carcinoma (SCC) and enhance oncogenic growth in vitro and in vivo. Moreover, p53 associated with DeltaNp63alpha and mediated its degradation. Here, we report that DeltaNp63 associates with the B56alpha regulatory subunit of protein phosphatase 2A (PP2A) and glycogen synthase kinase 3beta (GSK3beta), leading to a dramatic inhibition of PP2A-mediated GSK3beta reactivation. The inhibitory effect of DeltaNp63 on GSK3beta mediates a decrease in phosphorylation levels of beta-catenin, which induces intranuclear accumulation of beta-catenin and activates beta-catenin-dependent transcription. Our results suggest that DeltaNp63 isotypes act as positive regulators of the beta-catenin signaling pathway, providing a basis for their oncogenic properties.
Patturajan
Meera
M
Department of Otolaryngology-Head and Neck Surgery, John Hopkins School of Medicine, Baltimore, MD 21205, USA.
Nomoto
Shuji
S
Sommer
Matthias
M
Fomenkov
Alexey
A
Hibi
Kenji
K
Zangen
Rachel
R
Poliak
Nina
N
Califano
Joseph
J
Trink
Barry
B
Ratovitski
Edward
E
Sidransky
David
D
D001798:Blood Proteins / Q000235:genetics / Q000378:metabolism*; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism* / Q000494:pharmacology; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism* / Q000494:pharmacology; D016147:Genes, Tumor Suppressor; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D010750:Phosphoproteins; D010766:Phosphorylation; D010957:Plasmids; D011233:Precipitin Tests; D054648:Protein Phosphatase 2; D015398:Signal Transduction; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D020798:Two-Hybrid System Techniques; D051176:beta Catenin
C112123:B56 protein, human; D001798:Blood Proteins; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D010750:Phosphoproteins; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; D008156:Luciferases; D038341:Glycogen Synthase Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D004250:DNA Topoisomerases, Type II