PMID- 10618392
OWN - NLM
STAT- MEDLINE
DCOM- 20000210
LR  - 20190501
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 97
IP  - 1
DP  - 2000 Jan 4
TI  - Endogenous, hyperactive Rac3 controls proliferation of breast cancer cells by a
      p21-activated kinase-dependent pathway.
PG  - 185-9
AB  - Uncontrolled cell proliferation is a major feature of cancer. Experimental
      cellular models have implicated some members of the Rho GTPase family in this
      process. However, direct evidence for active Rho GTPases in tumors or cancer cell
      lines has never been provided. In this paper, we show that endogenous,
      hyperactive Rac3 is present in highly proliferative human breast cancer-derived
      cell lines and tumor tissues. Rac3 activity results from both its distinct
      subcellular localization at the membrane and altered regulatory factors affecting
      the guanine nucleotide state of Rac3. Associated with active Rac3 was
      deregulated, persistent kinase activity of two isoforms of the Rac effector
      p21-activated kinase (Pak) and of c-Jun N-terminal kinase (JNK). Introducing
      dominant-negative Rac3 and Pak1 fragments into a breast cancer cell line revealed
      that active Rac3 drives Pak and JNK kinase activities by two separate pathways.
      Only the Rac3-Pak pathway was critical for DNA synthesis, independently of JNK.
      These findings identify Rac3 as a consistently active Rho GTPase in human cancer 
      cells and suggest an important role for Rac3 and Pak in tumor growth.
FAU - Mira, J P
AU  - Mira JP
AD  - Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037,
      USA.
FAU - Benard, V
AU  - Benard V
FAU - Groffen, J
AU  - Groffen J
FAU - Sanders, L C
AU  - Sanders LC
FAU - Knaus, U G
AU  - Knaus UG
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (Trans-Activators)
RN  - 0 (Transcription Factors)
RN  - 9007-49-2 (DNA)
RN  - EC 2.3.1.48 (Nuclear Receptor Coactivator 3)
RN  - EC 2.7.11.1 (Protein-Serine-Threonine Kinases)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 3.6.5.2 (rho GTP-Binding Proteins)
SB  - IM
MH  - Breast Neoplasms
MH  - Cell Division
MH  - DNA/biosynthesis
MH  - Female
MH  - Gene Expression Regulation, Enzymologic/genetics
MH  - Gene Expression Regulation, Neoplastic/genetics
MH  - Humans
MH  - JNK Mitogen-Activated Protein Kinases
MH  - Microscopy, Fluorescence
MH  - Mitogen-Activated Protein Kinases/metabolism
MH  - Nuclear Receptor Coactivator 3
MH  - Protein-Serine-Threonine Kinases/genetics/*metabolism
MH  - Trans-Activators/genetics/*metabolism
MH  - *Transcription Factors
MH  - Transfection
MH  - Tumor Cells, Cultured
MH  - rho GTP-Binding Proteins/genetics
PMC - PMC26637
EDAT- 2000/01/05 00:00
MHDA- 2000/01/05 00:01
CRDT- 2000/01/05 00:00
PHST- 2000/01/05 00:00 [pubmed]
PHST- 2000/01/05 00:01 [medline]
PHST- 2000/01/05 00:00 [entrez]
AID - 10.1073/pnas.97.1.185 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2000 Jan 4;97(1):185-9. doi: 10.1073/pnas.97.1.185.