title: CD30 activates both the canonical and alternative NF-kappaB pathways in anaplastic large cell lymphoma cells.
abstract: CD30 is a member of the tumor necrosis factor receptor superfamily whose expression is up-regulated on anaplastic large cell lymphoma (ALCL) and Hodgkin lymphoma (HL) cells. Many different outcomes of CD30 stimulation have been reported, including cell cycle arrest, apoptosis, and activation of the prosurvival transcription factor, NF-kappaB, although this last activity is much less well defined in ALCL cells. In order to better understand the signaling properties of CD30 in cancer, we established a system for the stimulation of CD30 with its physiological ligand. Using this system, CD30 was stimulated on ALCL and HL cells, and the subsequent CD30 signaling properties were characterized. We show that a fraction of ALCL cells rapidly underwent apoptosis following CD30 stimulation, whereas HL cells were unaffected. The surviving ALCL cells exhibited robust activation of both the canonical and alternative NF-kappaB pathways as measured by nuclear translocation of RelA, p50, RelB, and p52, and this culminated in the transactivation of classical NF-kappaB-responsive genes. With prolonged CD30 stimulation, ALCL cells underwent cell cycle arrest that correlated with expression of the cell cycle inhibitor p21(waf1). Furthermore, p21(waf1) expression and cell cycle arrest were found to depend predominantly on the canonical NF-kappaB pathway, since it was reversed by RNA interference-mediated suppression of RelA. In contrast, suppression of the p100/p52 NF-kappaB subunit had little effect on p21(waf1). These data reveal that in ALCL cells, in contrast to other cell types, CD30 stimulation elicits p21(waf1)-mediated arrest through the canonical but not the alternative NF-kappaB pathway.
authors.affiliation: Department of Pathology, the Molecular Mechanisms of Disease Program, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Casey W
authors.initials: CW
authors.lastname: Wright
authors.forename: Julie M
authors.initials: JM
authors.lastname: Rumble
authors.forename: Colin S
authors.initials: CS
authors.lastname: Duckett
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics; D000818:Animals; D053285:CD30 Ligand / Q000378:metabolism* / Q000494:pharmacology; D016466:CHO Cells; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D006224:Cricetinae; D003412:Cricetulus; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D006689:Hodgkin Disease / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D017730:Ki-1 Antigen / Q000378:metabolism*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D034622:RNA Interference / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D053285:CD30 Ligand; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D017730:Ki-1 Antigen; D016328:NF-kappa B; C505774:TNFSF8 protein, human