PMID- 10523665
OWN - NLM
STAT- MEDLINE
DCOM- 19991124
LR  - 20190508
IS  - 0270-7306 (Print)
IS  - 0270-7306 (Linking)
VI  - 19
IP  - 11
DP  - 1999 Nov
TI  - Dependence of Dbl and Dbs transformation on MEK and NF-kappaB activation.
PG  - 7759-70
AB  - Dbs was identified initially as a transforming protein and is a member of the Dbl
      family of proteins (>20 mammalian members). Here we show that Dbs, like its rat
      homolog Ost and the closely related Dbl, exhibited guanine nucleotide exchange
      activity for the Rho family members RhoA and Cdc42, but not Rac1, in vitro. Dbs
      transforming activity was blocked by specific inhibitors of RhoA and Cdc42
      function, demonstrating the importance of these small GTPases in Dbs-mediated
      growth deregulation. Although Dbs transformation was dependent upon the
      structural integrity of its pleckstrin homology (PH) domain, replacement of the
      PH domain with a membrane localization signal restored transforming activity.
      Thus, the PH domain of Dbs (but not Dbl) may be important in modulating
      association with the plasma membrane, where its GTPase substrates reside. Both
      Dbs and Dbl activate multiple signaling pathways that include activation of the
      Elk-1, Jun, and NF-kappaB transcription factors and stimulation of transcription 
      from the cyclin D1 promoter. We found that Elk-1 and NF-kappaB, but not Jun,
      activation was necessary for Dbl and Dbs transformation. Finally, we have
      observed that Dbl and Dbs regulated transcription from the cyclin D1 promoter in 
      a NF-kappaB-dependent manner. Previous studies have dissociated actin
      cytoskeletal activity from the transforming potential of RhoA and Cdc42. These
      observations, when taken together with those of the present study, suggest that
      altered gene expression, and not actin reorganization, is the critical mediator
      of Dbl and Rho family protein transformation.
FAU - Whitehead, I P
AU  - Whitehead IP
AD  - Department of Microbiology, UMDNJ-New Jersey Medical School, Newark, New Jersey
      07103, USA.
FAU - Lambert, Q T
AU  - Lambert QT
FAU - Glaven, J A
AU  - Glaven JA
FAU - Abe, K
AU  - Abe K
FAU - Rossman, K L
AU  - Rossman KL
FAU - Mahon, G M
AU  - Mahon GM
FAU - Trzaskos, J M
AU  - Trzaskos JM
FAU - Kay, R
AU  - Kay R
FAU - Campbell, S L
AU  - Campbell SL
FAU - Der, C J
AU  - Der CJ
LA  - eng
GR  - R01 CA042978/CA/NCI NIH HHS/United States
GR  - CA63071/CA/NCI NIH HHS/United States
GR  - CA55008/CA/NCI NIH HHS/United States
GR  - CA42978/CA/NCI NIH HHS/United States
GR  - R01 CA063071/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (Guanine Nucleotide Exchange Factors)
RN  - 0 (Mcf2 protein, mouse)
RN  - 0 (Mcf2l protein, mouse)
RN  - 0 (Membrane Proteins)
RN  - 0 (NF-kappa B)
RN  - 0 (Retroviridae Proteins, Oncogenic)
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 (MAP Kinase Kinase 4)
RN  - EC 2.7.12.2 (Map2k1 protein, mouse)
RN  - EC 2.7.12.2 (Map2k4 protein, mouse)
RN  - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases)
RN  - EC 3.6.5.2 (cdc42 GTP-Binding Protein)
RN  - EC 3.6.5.2 (rhoA GTP-Binding Protein)
SB  - IM
MH  - 3T3 Cells
MH  - Animals
MH  - *Cell Transformation, Neoplastic
MH  - Guanine Nucleotide Exchange Factors/*metabolism
MH  - MAP Kinase Kinase 1
MH  - *MAP Kinase Kinase 4
MH  - Membrane Proteins
MH  - Mice
MH  - Mitogen-Activated Protein Kinase Kinases/*metabolism
MH  - NF-kappa B/*metabolism
MH  - Protein Structure, Tertiary
MH  - *Protein-Serine-Threonine Kinases
MH  - Retroviridae Proteins, Oncogenic/*metabolism
MH  - Signal Transduction
MH  - cdc42 GTP-Binding Protein/metabolism
MH  - rhoA GTP-Binding Protein/metabolism
PMC - PMC84831
EDAT- 1999/10/19 00:00
MHDA- 1999/10/19 00:01
CRDT- 1999/10/19 00:00
PHST- 1999/10/19 00:00 [pubmed]
PHST- 1999/10/19 00:01 [medline]
PHST- 1999/10/19 00:00 [entrez]
AID - 10.1128/mcb.19.11.7759 [doi]
PST - ppublish
SO  - Mol Cell Biol. 1999 Nov;19(11):7759-70. doi: 10.1128/mcb.19.11.7759.