PMID- 18094073
OWN - NLM
STAT- MEDLINE
DCOM- 20080407
LR  - 20211203
IS  - 1521-0111 (Electronic)
IS  - 0026-895X (Linking)
VI  - 73
IP  - 3
DP  - 2008 Mar
TI  - Interferon beta augments tuberous sclerosis complex 2 (TSC2)-dependent inhibition 
      of TSC2-null ELT3 and human lymphangioleiomyomatosis-derived cell proliferation.
PG  - 778-88
AB  - Lymphangioleiomyomatosis (LAM), a rare pulmonary disorder, manifests as an 
      abnormal neoplastic growth of smooth muscle-like cells within the lungs. 
      Mutational inactivation of tumor suppressor tuberous sclerosis complex 2 (TSC2) 
      in LAM constitutively activates the mammalian target of rapamycin (mTOR)/p70 S6 
      kinase 1 (S6K1) signaling pathway and promotes neoplastic growth of LAM cells. In 
      many cell types, type I interferon beta (IFNbeta) inhibits proliferation and 
      induces apoptosis through signal transducers and activators of transcription 
      (STAT)-dependent and STAT-independent signaling pathways, one of which is the 
      mTOR/S6K1 signaling pathway. Our study shows that IFNbeta is expressed in LAM 
      tissues and LAM-derived cell cultures; however, IFNbeta attenuates LAM-derived 
      cell proliferation only at high concentrations, 100 and 1000 U/ml (IC(50) value 
      for IFNbeta is 20 U/ml compared with 1 U/ml for normal human mesenchymal cells, 
      human bronchus fibroblasts and human airway smooth muscle cells). Likewise, 
      IFNbeta only attenuates proliferation of smooth muscle TSC2-null ELT3 cells. 
      Analysis of IFNbeta signaling in LAM cells showed expression of IFNbeta receptor 
      alpha (IFNbetaRalpha) and IFNbetaRbeta, activation and nuclear translocation of 
      STAT1, and phosphorylation of STAT3 and p38 mitogen-activated protein kinase 
      (MAPK), but IFNbeta had little effect on S6K1 activity. However, the 
      re-expression of TSC2 or inhibition of mTOR/S6K1 with rapamycin (sirolimus) 
      augmented antiproliferative effects of IFNbeta in LAM and TSC2-null ELT3 cells. 
      Our study demonstrates that IFNbeta-dependent activation of STATs and p38 MAPK is 
      not sufficient to fully inhibit proliferation of cells with TSC2 dysfunction and 
      that TSC2-dependent inhibition of mTOR/S6K1 cooperates with IFNbeta in inhibiting 
      human LAM and TSC2-null ELT3 cell proliferation.
FAU - Goncharova, Elena A
AU  - Goncharova EA
AD  - Department of Medicine, University of Pennsylvania, TRL Suite 1200, 125 South 
      31st Street, Philadelphia, PA 19104, USA. goncharo@mail.med.upenn.edu
FAU - Goncharov, Dmitry A
AU  - Goncharov DA
FAU - Chisolm, Amelia
AU  - Chisolm A
FAU - Spaits, Matthew S
AU  - Spaits MS
FAU - Lim, Poay N
AU  - Lim PN
FAU - Cesarone, Gregory
AU  - Cesarone G
FAU - Khavin, Irene
AU  - Khavin I
FAU - Tliba, Omar
AU  - Tliba O
FAU - Amrani, Yassine
AU  - Amrani Y
FAU - Panettieri, Reynold A Jr
AU  - Panettieri RA Jr
FAU - Krymskaya, Vera P
AU  - Krymskaya VP
LA  - eng
GR  - 2R01-HL071106/HL/NHLBI NIH HHS/United States
GR  - R01 HL090829/HL/NHLBI NIH HHS/United States
GR  - ES0135080/ES/NIEHS NIH HHS/United States
GR  - R00 HL089409-04/HL/NHLBI NIH HHS/United States
GR  - R00 HL089409/HL/NHLBI NIH HHS/United States
GR  - HL64063/HL/NHLBI NIH HHS/United States
GR  - HL55301/HL/NHLBI NIH HHS/United States
GR  - R01 HL071106/HL/NHLBI NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20071219
PL  - United States
TA  - Mol Pharmacol
JT  - Molecular pharmacology
JID - 0035623
RN  - 0 (Receptors, Interferon)
RN  - 0 (TSC2 protein, human)
RN  - 0 (Tsc2 protein, rat)
RN  - 0 (Tuberous Sclerosis Complex 2 Protein)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 147336-22-9 (Green Fluorescent Proteins)
RN  - 77238-31-4 (Interferon-beta)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Ribosomal Protein S6 Kinases, 70-kDa)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Cell Proliferation/*drug effects
MH  - Dose-Response Relationship, Drug
MH  - Drug Synergism
MH  - Female
MH  - Green Fluorescent Proteins/metabolism
MH  - Humans
MH  - Immunohistochemistry
MH  - Inhibitory Concentration 50
MH  - Interferon-beta/metabolism/*pharmacology
MH  - Leiomyoma/*pathology
MH  - Lymphangioleiomyomatosis/*metabolism/pathology
MH  - Muscle, Smooth/cytology/drug effects
MH  - Mutation
MH  - Phosphorylation/drug effects
MH  - Protein Kinases/metabolism
MH  - Rats
MH  - Receptors, Interferon/metabolism
MH  - Ribosomal Protein S6 Kinases, 70-kDa/antagonists & inhibitors
MH  - Signal Transduction
MH  - Sirolimus/pharmacology
MH  - Statistics as Topic
MH  - TOR Serine-Threonine Kinases
MH  - Tuberous Sclerosis Complex 2 Protein
MH  - Tumor Cells, Cultured
MH  - Tumor Suppressor Proteins/genetics/*metabolism
MH  - Uterine Neoplasms/*pathology
EDAT- 2007/12/21 09:00
MHDA- 2008/04/09 09:00
CRDT- 2007/12/21 09:00
PHST- 2007/12/21 09:00 [pubmed]
PHST- 2008/04/09 09:00 [medline]
PHST- 2007/12/21 09:00 [entrez]
AID - mol.107.040824 [pii]
AID - 10.1124/mol.107.040824 [doi]
PST - ppublish
SO  - Mol Pharmacol. 2008 Mar;73(3):778-88. doi: 10.1124/mol.107.040824. Epub 2007 Dec 
      19.