Journal
SURGERY
Volume 138, Issue 2, Pages 306-312Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.surg.2005.06.007
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Funding
- NCI NIH HHS [CA 68485, CA69457, R01 CA046413-18, R01 CA046413-19, R01 CA046413] Funding Source: Medline
- NIDDK NIH HHS [DK 52334] Funding Source: Medline
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Background. Loss of the cell membrane protein E-cadherin is a critical event during Ras-mediated transformation of intestinal epithelial cells. The purpose of our study is to determine if activation of the transcriptional repressor SLUG is an important component of the mechanism of Ras-induced loss of E-cadherin. Methods. Rat intestinal epithelial (RIE) cells were engineered to express mutated human Ha-Ras(Val12) complementary DNA (H-Ras cells). Cell morphology was examined by light microscopy. RNA and protein expression were measured by semiquantitative polymerase chain reaction and Western blot analyses, respectively. Short interfering RNA with 2 different oligos was used to knock down the expression of SLUG. Results. Oncogenic ras induces upregulation of the transcriptional repressor SLUG and subsequent downregutation of the junctional protein E-cadherin. Gene silencing of SLUG by short interfering RNA allows E-cadherin to be reexpressed. E-cadherin protein reexpression allows partial rescue of the transformed phenotype. Conclusion. These data suggest a mechanism whereby Ras signaling causes an upregulation of transcriptional repressors and subsequent downregulation of E-cadherin as a malignant phenotype is propagated.
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