Loss of Fnip1 alters kidney developmental transcriptional program and synergizes with TSC1 loss to promote mTORC1 activation and renal cyst formation

Ryan Centini, Mark Tsang, Terri Iwata, Heon Park, Jeffrey Delrow, Daciana Margineantu, Brandon M. Iritani, Haiwei Gu, H. Denny Liggitt, Janella Kang, Lim Kang, David M. Hockenbery, Daniel Raftery, Brian M. Iritani

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Birt-Hogg-Dube' Syndrome (BHDS) is a rare genetic disorder in humans characterized by skin hamartomas, lung cysts, pneumothorax, and increased risk of renal tumors. BHDS is caused by mutations in the BHD gene, which encodes for Folliculin, a cytoplasmic adapter protein that binds to Folliculin interacting proteins-1 and-2 (Fnip1, Fnip2) as well as the master energy sensor AMP kinase (AMPK). Whereas kidney-specific deletion of the Bhd gene in mice is known to result in polycystic kidney disease (PKD) and renal cell carcinoma, the roles of Fnip1 in renal cell development and function are unclear. In this study, we utilized mice with constitutive deletion of the Fnip1 gene to show that the loss of Fnip1 is sufficient to result in renal cyst formation, which was characterized by decreased AMPK activation, increased mTOR activation, and metabolic hyperactivation. Using RNAseq, we found that Fnip1 disruption resulted in many cellular and molecular changes previously implicated in the development of PKD in humans, including alterations in the expression of ion and amino acid transporters, increased cell adhesion, and increased inflammation. Loss of Fnip1 synergized with Tsc1 loss to hyperactivate mTOR, increase Erk activation, and greatly accelerate the development of PKD. Our results collectively define roles for Fnip1 in regulating kidney development and function, and provide a model for how loss of Fnip1 contributes to PKD and perhaps renal cell carcinoma.

Original languageEnglish (US)
Article number0197973
JournalPLoS One
Volume13
Issue number6
DOIs
StatePublished - Jun 1 2018

Fingerprint

Polycystic Kidney Diseases
Cysts
kidney cells
Chemical activation
kidneys
Birt-Hogg-Dube Syndrome
Kidney
Adenylate Kinase
AMP-activated protein kinase
estrone
gene deletion
Estrone
Genes
carcinoma
Gene Deletion
Renal Cell Carcinoma
Cells
hamartoma
pneumothorax
amino acid transporters

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Loss of Fnip1 alters kidney developmental transcriptional program and synergizes with TSC1 loss to promote mTORC1 activation and renal cyst formation. / Centini, Ryan; Tsang, Mark; Iwata, Terri; Park, Heon; Delrow, Jeffrey; Margineantu, Daciana; Iritani, Brandon M.; Gu, Haiwei; Liggitt, H. Denny; Kang, Janella; Kang, Lim; Hockenbery, David M.; Raftery, Daniel; Iritani, Brian M.

In: PLoS One, Vol. 13, No. 6, 0197973, 01.06.2018.

Research output: Contribution to journalArticle

Centini, R, Tsang, M, Iwata, T, Park, H, Delrow, J, Margineantu, D, Iritani, BM, Gu, H, Liggitt, HD, Kang, J, Kang, L, Hockenbery, DM, Raftery, D & Iritani, BM 2018, 'Loss of Fnip1 alters kidney developmental transcriptional program and synergizes with TSC1 loss to promote mTORC1 activation and renal cyst formation', PLoS One, vol. 13, no. 6, 0197973. https://doi.org/10.1371/journal.pone.0197973
Centini, Ryan ; Tsang, Mark ; Iwata, Terri ; Park, Heon ; Delrow, Jeffrey ; Margineantu, Daciana ; Iritani, Brandon M. ; Gu, Haiwei ; Liggitt, H. Denny ; Kang, Janella ; Kang, Lim ; Hockenbery, David M. ; Raftery, Daniel ; Iritani, Brian M. / Loss of Fnip1 alters kidney developmental transcriptional program and synergizes with TSC1 loss to promote mTORC1 activation and renal cyst formation. In: PLoS One. 2018 ; Vol. 13, No. 6.
@article{83c50c53284f4a4d8dbd3c629afd9d66,
title = "Loss of Fnip1 alters kidney developmental transcriptional program and synergizes with TSC1 loss to promote mTORC1 activation and renal cyst formation",
abstract = "Birt-Hogg-Dube' Syndrome (BHDS) is a rare genetic disorder in humans characterized by skin hamartomas, lung cysts, pneumothorax, and increased risk of renal tumors. BHDS is caused by mutations in the BHD gene, which encodes for Folliculin, a cytoplasmic adapter protein that binds to Folliculin interacting proteins-1 and-2 (Fnip1, Fnip2) as well as the master energy sensor AMP kinase (AMPK). Whereas kidney-specific deletion of the Bhd gene in mice is known to result in polycystic kidney disease (PKD) and renal cell carcinoma, the roles of Fnip1 in renal cell development and function are unclear. In this study, we utilized mice with constitutive deletion of the Fnip1 gene to show that the loss of Fnip1 is sufficient to result in renal cyst formation, which was characterized by decreased AMPK activation, increased mTOR activation, and metabolic hyperactivation. Using RNAseq, we found that Fnip1 disruption resulted in many cellular and molecular changes previously implicated in the development of PKD in humans, including alterations in the expression of ion and amino acid transporters, increased cell adhesion, and increased inflammation. Loss of Fnip1 synergized with Tsc1 loss to hyperactivate mTOR, increase Erk activation, and greatly accelerate the development of PKD. Our results collectively define roles for Fnip1 in regulating kidney development and function, and provide a model for how loss of Fnip1 contributes to PKD and perhaps renal cell carcinoma.",
author = "Ryan Centini and Mark Tsang and Terri Iwata and Heon Park and Jeffrey Delrow and Daciana Margineantu and Iritani, {Brandon M.} and Haiwei Gu and Liggitt, {H. Denny} and Janella Kang and Lim Kang and Hockenbery, {David M.} and Daniel Raftery and Iritani, {Brian M.}",
year = "2018",
month = "6",
day = "1",
doi = "10.1371/journal.pone.0197973",
language = "English (US)",
volume = "13",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "6",

}

TY - JOUR

T1 - Loss of Fnip1 alters kidney developmental transcriptional program and synergizes with TSC1 loss to promote mTORC1 activation and renal cyst formation

AU - Centini, Ryan

AU - Tsang, Mark

AU - Iwata, Terri

AU - Park, Heon

AU - Delrow, Jeffrey

AU - Margineantu, Daciana

AU - Iritani, Brandon M.

AU - Gu, Haiwei

AU - Liggitt, H. Denny

AU - Kang, Janella

AU - Kang, Lim

AU - Hockenbery, David M.

AU - Raftery, Daniel

AU - Iritani, Brian M.

PY - 2018/6/1

Y1 - 2018/6/1

N2 - Birt-Hogg-Dube' Syndrome (BHDS) is a rare genetic disorder in humans characterized by skin hamartomas, lung cysts, pneumothorax, and increased risk of renal tumors. BHDS is caused by mutations in the BHD gene, which encodes for Folliculin, a cytoplasmic adapter protein that binds to Folliculin interacting proteins-1 and-2 (Fnip1, Fnip2) as well as the master energy sensor AMP kinase (AMPK). Whereas kidney-specific deletion of the Bhd gene in mice is known to result in polycystic kidney disease (PKD) and renal cell carcinoma, the roles of Fnip1 in renal cell development and function are unclear. In this study, we utilized mice with constitutive deletion of the Fnip1 gene to show that the loss of Fnip1 is sufficient to result in renal cyst formation, which was characterized by decreased AMPK activation, increased mTOR activation, and metabolic hyperactivation. Using RNAseq, we found that Fnip1 disruption resulted in many cellular and molecular changes previously implicated in the development of PKD in humans, including alterations in the expression of ion and amino acid transporters, increased cell adhesion, and increased inflammation. Loss of Fnip1 synergized with Tsc1 loss to hyperactivate mTOR, increase Erk activation, and greatly accelerate the development of PKD. Our results collectively define roles for Fnip1 in regulating kidney development and function, and provide a model for how loss of Fnip1 contributes to PKD and perhaps renal cell carcinoma.

AB - Birt-Hogg-Dube' Syndrome (BHDS) is a rare genetic disorder in humans characterized by skin hamartomas, lung cysts, pneumothorax, and increased risk of renal tumors. BHDS is caused by mutations in the BHD gene, which encodes for Folliculin, a cytoplasmic adapter protein that binds to Folliculin interacting proteins-1 and-2 (Fnip1, Fnip2) as well as the master energy sensor AMP kinase (AMPK). Whereas kidney-specific deletion of the Bhd gene in mice is known to result in polycystic kidney disease (PKD) and renal cell carcinoma, the roles of Fnip1 in renal cell development and function are unclear. In this study, we utilized mice with constitutive deletion of the Fnip1 gene to show that the loss of Fnip1 is sufficient to result in renal cyst formation, which was characterized by decreased AMPK activation, increased mTOR activation, and metabolic hyperactivation. Using RNAseq, we found that Fnip1 disruption resulted in many cellular and molecular changes previously implicated in the development of PKD in humans, including alterations in the expression of ion and amino acid transporters, increased cell adhesion, and increased inflammation. Loss of Fnip1 synergized with Tsc1 loss to hyperactivate mTOR, increase Erk activation, and greatly accelerate the development of PKD. Our results collectively define roles for Fnip1 in regulating kidney development and function, and provide a model for how loss of Fnip1 contributes to PKD and perhaps renal cell carcinoma.

UR - http://www.scopus.com/inward/record.url?scp=85048959262&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85048959262&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0197973

DO - 10.1371/journal.pone.0197973

M3 - Article

VL - 13

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 6

M1 - 0197973

ER -