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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Nat+Commun
2016 ; 7
(ä): 10786
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mTORC1-mediated inhibition of polycystin-1 expression drives renal cyst formation
in tuberous sclerosis complex
#MMPMID26931735
Pema M
; Drusian L
; Chiaravalli M
; Castelli M
; Yao Q
; Ricciardi S
; Somlo S
; Qian F
; Biffo S
; Boletta A
Nat Commun
2016[Mar]; 7
(ä): 10786
PMID26931735
show ga
Previous studies report a cross-talk between the polycystic kidney disease (PKD)
and tuberous sclerosis complex (TSC) genes. mTOR signalling is upregulated in PKD
and rapamycin slows cyst expansion, whereas renal inactivation of the Tsc genes
causes cysts. Here we identify a new interplay between the PKD and TSC genes,
with important implications for the pathophysiology of both diseases.
Kidney-specific inactivation of either Pkd1 or Tsc1 using an identical Cre
(KspCre) results in aggressive or very mild PKD, respectively. Unexpectedly, we
find that mTORC1 negatively regulates the biogenesis of polycystin-1 (PC-1) and
trafficking of the PC-1/2 complex to cilia. Genetic interaction studies reveal an
important role for PC-1 downregulation by mTORC1 in the cystogenesis of Tsc1
mutants. Our data potentially explain the severe renal manifestations of the
TSC/PKD contiguous gene syndrome and open new perspectives for the use of mTOR
inhibitors in autosomal dominant PKD caused by hypomorphic or missense PKD1
mutations.