NF-kappaB activation is required for apoptosis in fibrocystin/polyductin-depleted kidney epithelial cells.
Autosomal recessive polycystic kidney disease (ARPKD) is caused by mutations in PKHD1, a gene encoding fibrocystin/polyductin (FC1), a membrane-associated receptor-like protein involved in the regulation of tubular cell adhesion, proliferation and apoptosis. Although it is generally accepted that apoptosis is implicated in ARPKD, the question of whether increased apoptosis is a normal response to abnormal cell proliferation or, instead, it is a primary event, is still subject to debate. In support of the latter hypothesis, we hereby provide evidence that apoptosis occurs in the absence of hyper-proliferation of FC1-depleted kidney cells. In fact, a decrease in cell proliferation, with a concomitant increase in apoptotic index and caspase-3 activity was observed in response to FC1-depletion by PKHD1 siRNA silencing in HEK293 and 4/5 tubular cells. FC1-depletion also induced reduction in ERK1/2 kinase activation, upregulation of the pro-apoptotic protein p53 and activation of NF-kappaB, a transcription factor which reduces apoptosis in many organs and tissues. Interestingly, selective inactivation of NF-kappaB using either an NF-kappaB decoy or parthenolide, a blocker of IKK-dependent NF-kappaB activation, reduced, rather then increased, apoptosis and p53 levels in FC1-depleted cells. Therefore, the proapoptotic function of NF-kappaB during cell death by FC1-depletion in kidney cells is evident.
Mangolini
Alessandra
A
Department of Biochemistry and Molecular Biology, University of Ferrara, 44100 Ferrara, Italy.
Bogo
Marco
M
Durante
Chiara
C
Borgatti
Monica
M
Gambari
Roberto
R
Harris
Peter C
PC
Rizzuto
Rosario
R
Pinton
Paolo
P
Aguiari
Gianluca
G
del Senno
Laura
L
D017209:Apoptosis; D002453:Cell Cycle; D002460:Cell Line; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000166:cytology* / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D017044:Polycystic Kidney, Autosomal Recessive / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D016328:NF-kappa B; C451750:PKHD1 protein, human; D011956:Receptors, Cell Surface; D048049:Extracellular Signal-Regulated MAP Kinases