Download Primary Cilium and Tumor Suppression

Primary Cilium and Tumor Suppression
Yu Jiang, Ph.D.
Department of Pharmacology and Chemical Biology,
University of Pittsburgh
Primary Cilium
(Nat Rev Mol Cell Biol 3: 813–25)
Primary Cilium and Cell Cycle
Resting Phase
Cycling Phase
(Adapted from Nat Rev Mol Cell Biol 3: 813–25)
Birt Hogg Dube Syndrome
●
●
A rare genetic disease predisposing patients to
developing cystic kidney, renal cell carcinomas,
fibrofolliculomas, spontaneous pneumothorax and lung
cysts.
The syndrome is caused by germline mutations in the
BHD gene, which encodes the tumor-suppressor protein
folliculin (FLCN).
BHD Skin Lesions: Fibrofolliculomas
(www.bhdsyndrome.org)
Polycystic Kidneys in FLCN Deficient Mice
(Chen J et al. PLoS one. Oct 30. 2008)
Kinesin 2
KIF-3A
KIF-3B
(Annu Rev Cell Dev Biol 29:443-69)
Ciliary Localization of FLCN
Acet. tub
Ctrl
Dox
FLCN
Merge
Structure of Primary Cilium
acet-tubulin
γ-tubulin
(Nat Rev Mol Cell Biol 3: 813–25)
Flow System
(Kotosis et al 2008 )
FLCN inhibits mTORC1 activity through primary cilia
in QUIESCENT cells
FLOW
Primary Cilium
FLCN
LKB1
AMPK
mTORC1
FLCN recruits LKB1 to primary cilia in response to flow
Acet. tubulin
WT
WT
KD
LKB1
M erge
FLCN is required for flow induced AMPK activation
Acet. tubulin
WT
Flow
WT
KD
P -AM P K
M erge
Flow activates AMPK on the basal body
γ-tubulin
WT
WT
KD
P-AMPK
M erge
Cilium-Dependent interaction of FLCN with LKB1
Action of FLCN in Primary Cilia
FLCN
LKB1
LKB1
FLCN
LKB1
FLOW
FLCN
LKB1
FLCN
LKB1
FLCN
LKB1
AMPK
AMPK
AMPK
A Working Model for the Action of FLCN in Primary Cilia
Oncogenic Signals
FLCN
Soluble
Passenger
Tumor suppressors
Train
Flow
Acknowledgement
Xuwen Zhao
Mingming Zhong
Venetta Suvlia
Ora Weisz
Department of Medicine,
University of Pittsburgh
Susan Ferro-Novick, UCSD
Jinmei Li
Shuguang Guo
Yichao Chu
Yulong Zhang
Xiaochun Bai, Southern
Medical University, China
Yongjian Liu, Nanjing Medical
University, China
NIH
CA169186