Constitutive RelA activation mediated by Nkx3.2 controls chondrocyte viability.
During endochondral ossification, a process that accounts for the majority of bone formation in vertebrates, hypertrophic chondrocytes display a greater susceptibility to apoptosis when compared to proliferating chondrocytes. However, the molecular mechanisms underlying this phenomenon remain unclear. Nkx3.2, a member of the NK class of homeoproteins, is initially expressed in chondrogenic precursor cells, and later, during cartilage maturation, its expression is restricted to proliferating chondrocytes. Here, we show that the nuclear factor kappa B (NF-kappaB) pathway is required for chondrocyte viability and that Nkx3.2 supports chondrocyte survival by constitutively activating RelA. Although signal-dependent NF-kappaB activation has been intensively studied, ligand-independent NF-kappaB activation is poorly understood. The data presented here support a novel ligand-independent mechanism of NF-kappaB activation, whereby Nkx3.2 recruits the RelA-IkappaBalpha heteromeric complex into the nucleus by direct protein-protein interactions and activates RelA through proteasome-dependent IkappaBalpha degradation in the nucleus. Furthermore, we demonstrate that stage-specific NF-kappaB activation, mediated by Nkx3.2, regulates chondrocyte viability during cartilage maturation.
Park
Minsun
M
Department of Biochemistry, Yonsei University, SEOUL, 120-749, Republic of Korea.
Yong
Yeryoung
Y
Choi
Seung-Won
SW
Kim
Jae Hwan
JH
Lee
Jong Eun
JE
Kim
Dae-Won
DW
D021581:Active Transport, Cell Nucleus; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D019902:Chondrocytes / Q000166:cytology / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000378:metabolism; D047468:Immunoprecipitation; D051379:Mice; D009154:Mutation; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D025801:Ubiquitin / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
C494812:Bcl2l1 protein, mouse; D018398:Homeodomain Proteins; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; C107965:Nkx3-2 protein, mouse; D034741:RNA, Small Interfering; C498144:Rela protein, mouse; D051996:Transcription Factor RelA; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; D051020:bcl-X Protein; D000072000:NF-KappaB Inhibitor alpha; D009599:Nitroprusside; D053148:Caspase 3; D046988:Proteasome Endopeptidase Complex