Inducible expression of RbAp46 activates c-Jun NH2-terminal kinase-dependent apoptosis and suppresses progressive growth of tumor xenografts in nude mice.
BACKGROUND
The retinoblastoma (Rb) suppressor-associated protein 46 (RbAp46) is a member of the WD-repeat protein family and a component of histone modifying and remodeling complexes. Previously, we demonstrated that RbAp46 inhibits cell growth and suppresses the transformed phenotypes of tumor cell lines.


METHODS
We established a tetracycline-inducible RbAp46 expression system in Saos-2 cells to test the effects of RbAp46 induction on cell growth in vitro and on tumor formation in vivo.


RESULTS
We found that inducible expression of RbAp46 activated the c-Jun N-terminal kinase (JNK) signaling pathway and triggered apoptosis in Saos-2 cells. A dominant-negative mutant of JNK1, which can inhibit RbAp46-induced JNK activity, blocked RbAp46-mediated apoptosis. We also found that the induction of RbAp46 expression strongly suppressed the formation of tumors grafted in nude mice and drastically reduced growth of established tumor xenografts.


CONCLUSIONS
These results revealed a novel proapoptotic activity for RbAp46 via the JNK pathway and demonstrated that induction of RbAp46 expression inhibits progressive growth of tumor grafts in vivo.
Cancer Center, Creighton University, 2500 California Plaza, Omaha, NE 68178, USA.
Teng-Fei
TF
Zhang
Shui-Qing
SQ
Yu
Brian W
BW
Loggie
Zhao-Yi
ZY
Wang
D000818:Animals; D017209:Apoptosis; D001859:Bone Neoplasms / Q000201:enzymology / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology; D002455:Cell Division; D004789:Enzyme Activation; D005134:Eye Neoplasms / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics* / Q000502:physiology; D012516:Osteosarcoma / Q000201:enzymology / Q000473:pathology*; D012175:Retinoblastoma / Q000235:genetics; D056524:Retinoblastoma-Binding Protein 7; D014183:Transplantation, Heterologous
D002352:Carrier Proteins; D009687:Nuclear Proteins; C490746:RBBP7 protein, human; C096378:Rbbp7 protein, mouse; D056524:Retinoblastoma-Binding Protein 7; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases