PMID- 10498890
OWN - NLM
STAT- MEDLINE
DCOM- 19991029
LR  - 20071114
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 18
IP  - 39
DP  - 1999 Sep 23
TI  - The TGF-beta signaling inhibitor Smad7 enhances tumorigenicity in pancreatic
      cancer.
PG  - 5363-72
AB  - Transforming growth factor-beta (TGF-beta) signaling is dependent on the
      heterodimerization of the type II TGF-beta receptor (TbetaRII) with the type I
      TGF-beta receptor (TbetaRI). Activated TbetaRI then mediates TGF-beta signals by 
      inducing the phosphorylation of Smad2 and/or Smad3, which separately
      hetetorodimerize with Smad4 and translocate to the nucleus. Phosphorylation of
      Smad2/Smad3 by activated TbetaRI is inhibited by two newly discovered members of 
      the Smad family, Smad6 and Smad7. We now report that Smad7 mRNA levels are
      increased in human pancreatic cancer by comparison with the normal pancreas, and 
      that by in situ hybridization, Smad7 is over-expressed in the cancer cells within
      the tumor mass. Stable transfection of COLO-357 human pancreatic cancer cells
      with a full-length Smad7 construct leads to complete loss of the growth
      inhibitory response to TGF-beta1, without altering TGF-beta1-mediated induction
      of PAI-I. Furthermore, Smad7 transfected COLO-357 cells display enhanced
      anchorage-independent growth and accelerated growth in nude mice. These findings 
      point to a previously unrecognized mechanism for selective suppression of
      TGF-beta-mediated growth inhibition in cancer cells that allows for continued
      activation of the PAI-I promoter by TGF-beta1, which may act to enhance the
      tumorigenicity of certain cancer cells.
FAU - Kleeff, J
AU  - Kleeff J
AD  - Division of Endocrinology, Diabetes, and Metabolism, Departments of Medicine,
      Biological Chemistry and Pharmacology, University of California, Irvine,
      California, CA 92697, USA.
FAU - Ishiwata, T
AU  - Ishiwata T
FAU - Maruyama, H
AU  - Maruyama H
FAU - Friess, H
AU  - Friess H
FAU - Truong, P
AU  - Truong P
FAU - Buchler, M W
AU  - Buchler MW
FAU - Falb, D
AU  - Falb D
FAU - Korc, M
AU  - Korc M
LA  - eng
GR  - CA75059/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Plasminogen Activator Inhibitor 1)
RN  - 0 (RNA, Messenger)
RN  - 0 (SMAD7 protein, human)
RN  - 0 (Smad7 Protein)
RN  - 0 (Smad7 protein, mouse)
RN  - 0 (Trans-Activators)
RN  - 0 (Transforming Growth Factor beta)
SB  - IM
MH  - Adolescent
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Animals
MH  - Cell Division
MH  - DNA-Binding Proteins/biosynthesis/genetics/*metabolism
MH  - Female
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - Male
MH  - Mice
MH  - Mice, Nude
MH  - Middle Aged
MH  - Neoplasm Transplantation
MH  - Pancreas/metabolism
MH  - Pancreatic Neoplasms/*metabolism/pathology
MH  - Plasminogen Activator Inhibitor 1
MH  - RNA, Messenger/metabolism
MH  - *Signal Transduction
MH  - Smad7 Protein
MH  - Trans-Activators/biosynthesis/genetics/*metabolism
MH  - Transforming Growth Factor beta/*antagonists & inhibitors/*metabolism
MH  - Tumor Cells, Cultured
EDAT- 1999/09/28 00:00
MHDA- 1999/09/28 00:01
CRDT- 1999/09/28 00:00
PHST- 1999/09/28 00:00 [pubmed]
PHST- 1999/09/28 00:01 [medline]
PHST- 1999/09/28 00:00 [entrez]
AID - 10.1038/sj.onc.1202909 [doi]
PST - ppublish
SO  - Oncogene. 1999 Sep 23;18(39):5363-72. doi: 10.1038/sj.onc.1202909.