Abstract |
The Rho GDP dissociation inhibitor D4-GDI is overexpressed in some human breast cancer cell lines (Zhang, Y., and Zhang, B. (2006) Cancer Res. 66, 5592-5598). Here, we show that silencing of D4-GDI by RNA interference abrogates tumor growth and lung metastasis of otherwise highly invasive MDA-MB-231 breast cancer cells. Under anchorage-independent culture conditions, D4-GDI-depleted cells undergo rapid apoptosis (anoikis), which is known to hinder metastasis. We also found that D4-GDI associates with Rac1 and Rac3 in breast cancer cells, but not with other Rho GTPases tested (Cdc42, RhoA, RhoC, and TC10). Silencing of D4-GDI results in constitutive Rac1 activation and translocation from the cytosol to cellular membrane compartments and in sustained activation of p38 and JNK kinases. Rac1 blockade inhibits p38/ JNK kinase activities and the spontaneous anoikis of D4-GDI knockdown cells. These results suggest that D4-GDI regulates cell function by interacting primarily with Rac GTPases and may play an integral role in breast cancer tumorigenesis. D4-GDI could prove to be a potential new target for therapeutic intervention.
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Authors | Yaqin Zhang, Leslie A Rivera Rosado, Sun Young Moon, Baolin Zhang |
Journal | The Journal of biological chemistry
(J Biol Chem)
Vol. 284
Issue 19
Pg. 12956-65
(May 08 2009)
ISSN: 0021-9258 [Print] United States |
PMID | 19269969
(Publication Type: Journal Article)
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Chemical References |
- ARHGDIB protein, human
- Guanine Nucleotide Dissociation Inhibitors
- RAC1 protein, human
- RNA, Small Interfering
- Tumor Suppressor Proteins
- rho Guanine Nucleotide Dissociation Inhibitor beta
- rho-Specific Guanine Nucleotide Dissociation Inhibitors
- JNK Mitogen-Activated Protein Kinases
- p38 Mitogen-Activated Protein Kinases
- rac1 GTP-Binding Protein
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Topics |
- Animals
- Anoikis
- Apoptosis
- Blotting, Western
- Breast Neoplasms
(metabolism, pathology, prevention & control)
- Cell Adhesion
- Cell Line, Tumor
- Cell Movement
- Cell Proliferation
- Female
- Gene Silencing
(physiology)
- Guanine Nucleotide Dissociation Inhibitors
(genetics)
- Humans
- Immunoprecipitation
- JNK Mitogen-Activated Protein Kinases
(metabolism)
- Lung Neoplasms
(metabolism, prevention & control, secondary)
- Mice
- Mice, Nude
- Neoplasm Invasiveness
- RNA, Small Interfering
(pharmacology)
- Signal Transduction
- Tumor Suppressor Proteins
(genetics)
- p38 Mitogen-Activated Protein Kinases
(metabolism)
- rac1 GTP-Binding Protein
(genetics, metabolism)
- rho Guanine Nucleotide Dissociation Inhibitor beta
- rho-Specific Guanine Nucleotide Dissociation Inhibitors
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