PMID- 10197981
OWN - NLM
STAT- MEDLINE
DCOM- 19990513
LR  - 20210108
IS  - 0890-9369 (Print)
IS  - 0890-9369 (Linking)
VI  - 13
IP  - 7
DP  - 1999 Apr 1
TI  - A mechanism of repression of TGFbeta/ Smad signaling by oncogenic Ras.
PG  - 804-16
AB  - TGFbeta can override the proliferative effects of EGF and other Ras-activating
      mitogens in normal epithelial cells. However, epithelial cells harboring
      oncogenic Ras mutations often show a loss of TGFbeta antimitogenic responses.
      Here we report that oncogenic Ras inhibits TGFbeta signaling in mammary and lung 
      epithelial cells by negatively regulating the TGFbeta mediators Smad2 and Smad3. 
      Oncogenically activated Ras inhibits the TGFbeta-induced nuclear accumulation of 
      Smad2 and Smad3 and Smad-dependent transcription. Ras acting via Erk MAP kinases 
      causes phosphorylation of Smad2 and Smad3 at specific sites in the region linking
      the DNA-binding domain and the transcriptional activation domain. These sites are
      separate from the TGFbeta receptor phosphorylation sites that activate Smad
      nuclear translocation. Mutation of these MAP kinase sites in Smad3 yields a
      Ras-resistant form that can rescue the growth inhibitory response to TGFbeta in
      Ras-transformed cells. EGF, which is weaker than oncogenic mutations at
      activating Ras, induces a less extensive phosphorylation and cytoplasmic
      retention of Smad2 and Smad3. Our results suggest a mechanism for the
      counterbalanced regulation of Smad2/Smad3 by TGFbeta and Ras signals in normal
      cells, and for the silencing of antimitogenic TGFbeta functions by hyperactive
      Ras in cancer cells.
FAU - Kretzschmar, M
AU  - Kretzschmar M
AD  - Cell Biology Program and Howard Hughes Medical Institute, Memorial
      Sloan-Kettering Cancer Center, New York, New York 10021 USA.
FAU - Doody, J
AU  - Doody J
FAU - Timokhina, I
AU  - Timokhina I
FAU - Massague, J
AU  - Massague J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Genes Dev
JT  - Genes & development
JID - 8711660
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (SMAD2 protein, human)
RN  - 0 (SMAD3 protein, human)
RN  - 0 (Smad2 Protein)
RN  - 0 (Smad3 Protein)
RN  - 0 (Trans-Activators)
RN  - 0 (Transforming Growth Factor beta)
RN  - EC 1.13.12.- (Luciferases)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
RN  - EC 2.7.12.2 (MAP Kinase Kinase 1)
RN  - EC 2.7.12.2 (MAP2K1 protein, human)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
RN  - EC 3.6.5.2 (ras Proteins)
SB  - IM
MH  - Animals
MH  - COS Cells
MH  - Cell Line
MH  - Cell Nucleus/metabolism
MH  - Cell Transformation, Neoplastic
MH  - Colonic Neoplasms/metabolism
MH  - DNA-Binding Proteins/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Humans
MH  - Luciferases/metabolism
MH  - MAP Kinase Kinase 1
MH  - *Mitogen-Activated Protein Kinase Kinases
MH  - Models, Genetic
MH  - Phosphorylation
MH  - Protein-Serine-Threonine Kinases/antagonists & inhibitors/metabolism
MH  - Protein-Tyrosine Kinases/antagonists & inhibitors/metabolism
MH  - Signal Transduction
MH  - Smad2 Protein
MH  - Smad3 Protein
MH  - Time Factors
MH  - Trans-Activators/metabolism
MH  - Transfection
MH  - Transforming Growth Factor beta/antagonists & inhibitors/*metabolism
MH  - Tumor Cells, Cultured
MH  - ras Proteins/*metabolism
PMC - PMC316599
EDAT- 1999/04/10 00:00
MHDA- 1999/04/10 00:01
CRDT- 1999/04/10 00:00
PHST- 1999/04/10 00:00 [pubmed]
PHST- 1999/04/10 00:01 [medline]
PHST- 1999/04/10 00:00 [entrez]
AID - 10.1101/gad.13.7.804 [doi]
PST - ppublish
SO  - Genes Dev. 1999 Apr 1;13(7):804-16. doi: 10.1101/gad.13.7.804.