PMID- 28030567
OWN - NLM
STAT- MEDLINE
DCOM- 20170706
LR  - 20181113
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 11
IP  - 12
DP  - 2016
TI  - Tumor-Derived Suppressor of Fused Mutations Reveal Hedgehog Pathway Interactions.
PG  - e0168031
LID - 10.1371/journal.pone.0168031 [doi]
LID - e0168031
AB  - The Hedgehog pathway is a potent regulator of cellular growth and plays a central 
      role in the development of many cancers including basal cell carcinoma (BCC). The 
      majority of BCCs arise from mutations in the Patched receptor resulting in 
      constitutive activation of the Hedgehog pathway. Secondary driver mutations 
      promote BCC oncogenesis and occur frequently due to the high mutational burden 
      resulting from sun exposure of the skin. Here, we uncover novel secondary 
      mutations in Suppressor of Fused (SUFU), the major negative regulator of the 
      Hedgehog pathway. SUFU normally binds to a Hedgehog transcriptional activator, 
      GLI1, in order to prevent it from initiating transcription of Hedgehog target 
      genes. We sequenced tumor-normal pairs from patients with early sporadic BCCs. 
      This resulted in the discovery of nine mutations in SUFU, which were functionally 
      investigated to determine whether they help drive BCC formation. Our results show 
      that four of the SUFU mutations inappropriately activate the Hedgehog pathway, 
      suggesting they may act as driver mutations for BCC development. Indeed, all four 
      of the loss of function SUFU variants were found to disrupt its binding to GLI, 
      leading to constitutive pathway activation. Our results from functional 
      characterization of these mutations shed light on SUFU's role in Hedgehog 
      signaling, tumor progression, and highlight a way in which BCCs can arise.
FAU - Urman, Nicole M
AU  - Urman NM
AD  - Program in Epithelial Biology and Department of Dermatology, Stanford University 
      School of Medicine, Stanford, CA, United States of America.
FAU - Mirza, Amar
AU  - Mirza A
AD  - Program in Epithelial Biology and Department of Dermatology, Stanford University 
      School of Medicine, Stanford, CA, United States of America.
FAU - Atwood, Scott X
AU  - Atwood SX
AD  - Program in Epithelial Biology and Department of Dermatology, Stanford University 
      School of Medicine, Stanford, CA, United States of America.
AD  - Department of Developmental and Cell Biology, Chao Family Comprehensive Cancer 
      Center, University of California, Irvine, Irvine, CA, United States of America.
FAU - Whitson, Ramon J
AU  - Whitson RJ
AD  - Program in Epithelial Biology and Department of Dermatology, Stanford University 
      School of Medicine, Stanford, CA, United States of America.
FAU - Sarin, Kavita Y
AU  - Sarin KY
AD  - Program in Epithelial Biology and Department of Dermatology, Stanford University 
      School of Medicine, Stanford, CA, United States of America.
FAU - Tang, Jean Y
AU  - Tang JY
AD  - Program in Epithelial Biology and Department of Dermatology, Stanford University 
      School of Medicine, Stanford, CA, United States of America.
FAU - Oro, Anthony E
AU  - Oro AE
AD  - Program in Epithelial Biology and Department of Dermatology, Stanford University 
      School of Medicine, Stanford, CA, United States of America.
LA  - eng
GR  - R00 CA176847/CA/NCI NIH HHS/United States
GR  - R01 AR046786/AR/NIAMS NIH HHS/United States
GR  - R01 AR054780/AR/NIAMS NIH HHS/United States
PT  - Journal Article
DEP - 20161228
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Hedgehog Proteins)
RN  - 0 (Repressor Proteins)
RN  - 0 (SUFU protein, human)
RN  - 0 (Zinc Finger Protein GLI1)
SB  - IM
MH  - Animals
MH  - Carcinogenesis
MH  - Carcinoma, Basal Cell/genetics/*metabolism/pathology
MH  - Cell Proliferation
MH  - Disease Progression
MH  - HEK293 Cells
MH  - Hedgehog Proteins/*metabolism
MH  - Humans
MH  - Mice
MH  - Models, Molecular
MH  - *Mutation
MH  - NIH 3T3 Cells
MH  - Protein Conformation
MH  - Repressor Proteins/chemistry/*genetics/*metabolism
MH  - *Signal Transduction
MH  - Skin Neoplasms/genetics/*metabolism/pathology
MH  - Young Adult
MH  - Zinc Finger Protein GLI1/metabolism
PMC - PMC5193403
COIS- The authors have declared that no competing interests exist.
EDAT- 2016/12/29 06:00
MHDA- 2017/07/07 06:00
PMCR- 2016/12/28
CRDT- 2016/12/29 06:00
PHST- 2016/06/14 00:00 [received]
PHST- 2016/11/23 00:00 [accepted]
PHST- 2016/12/29 06:00 [entrez]
PHST- 2016/12/29 06:00 [pubmed]
PHST- 2017/07/07 06:00 [medline]
PHST- 2016/12/28 00:00 [pmc-release]
AID - PONE-D-16-23850 [pii]
AID - 10.1371/journal.pone.0168031 [doi]
PST - epublish
SO  - PLoS One. 2016 Dec 28;11(12):e0168031. doi: 10.1371/journal.pone.0168031. 
      eCollection 2016.