PAI-1 Expression Is Required for HDACi-Induced Proliferative Arrest in ras-Transformed Renal Epithelial Cells
Malignant transformation of mammalian cells with ras family oncogenes results in dramatic changes in cellular architecture and growth traits. The generation of flat revertants of v-K-ras-transformed renal cells by exposure to the histone deacetylase inhibitor sodium butyrate (NaB) was previously fou...
Saved in:
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2011-01-01
|
| Series: | International Journal of Cell Biology |
| Online Access: | http://dx.doi.org/10.1155/2011/710974 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832561707841486848 |
|---|---|
| author | Stephen P. Higgins Craig E. Higgins Paul J. Higgins |
| author_facet | Stephen P. Higgins Craig E. Higgins Paul J. Higgins |
| author_sort | Stephen P. Higgins |
| collection | DOAJ |
| description | Malignant transformation of mammalian cells with ras family oncogenes results in dramatic changes in cellular architecture and growth traits. The generation of flat revertants of v-K-ras-transformed renal cells by exposure to the histone deacetylase inhibitor sodium butyrate (NaB) was previously found to be dependent on transcriptional activation of the PAI-1 (SERPINE1) gene (encoding the type-1 inhibitor of urokinase and tissue-type plasminogen activators). NaB-initiated PAI-1 expression preceded induced cell spreading and entry into G1 arrest. To assess the relevance of PAI-1 induction to growth arrest in this cell system more critically, two complementary approaches were used. The addition of a stable, long half-life, recombinant PAI-1 mutant to PAI-1-deficient v-K-ras-/c-Ha-ras-transformants or to PAI-1 functionally null, NaB-resistant, 4HH cells (engineered by antisense knockdown of PAI-1 mRNA transcripts) resulted in marked cytostasis in the absence of NaB. The transfection of ras-transformed cells with the Rc/CMVPAI expression construct, moreover, significantly elevated constitutive PAI-1 synthesis (10- to 20-fold) with a concomitant reduction in proliferative rate. These data suggest that high-level PAI-1 expression suppresses growth of chronic ras-oncogene transformed cells and is likely a major cytostatic effector of NaB exposure. |
| format | Article |
| id | doaj-art-631076cf7dcd4c318b3302feca58e40d |
| institution | Kabale University |
| issn | 1687-8876 1687-8884 |
| language | English |
| publishDate | 2011-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | International Journal of Cell Biology |
| spelling | doaj-art-631076cf7dcd4c318b3302feca58e40d2025-02-03T01:24:24ZengWileyInternational Journal of Cell Biology1687-88761687-88842011-01-01201110.1155/2011/710974710974PAI-1 Expression Is Required for HDACi-Induced Proliferative Arrest in ras-Transformed Renal Epithelial CellsStephen P. Higgins0Craig E. Higgins1Paul J. Higgins2Center for Cell Biology and Cancer Research, Albany Medical College (MC-165), Albany, NY 12208, USACenter for Cell Biology and Cancer Research, Albany Medical College (MC-165), Albany, NY 12208, USACenter for Cell Biology and Cancer Research, Albany Medical College (MC-165), Albany, NY 12208, USAMalignant transformation of mammalian cells with ras family oncogenes results in dramatic changes in cellular architecture and growth traits. The generation of flat revertants of v-K-ras-transformed renal cells by exposure to the histone deacetylase inhibitor sodium butyrate (NaB) was previously found to be dependent on transcriptional activation of the PAI-1 (SERPINE1) gene (encoding the type-1 inhibitor of urokinase and tissue-type plasminogen activators). NaB-initiated PAI-1 expression preceded induced cell spreading and entry into G1 arrest. To assess the relevance of PAI-1 induction to growth arrest in this cell system more critically, two complementary approaches were used. The addition of a stable, long half-life, recombinant PAI-1 mutant to PAI-1-deficient v-K-ras-/c-Ha-ras-transformants or to PAI-1 functionally null, NaB-resistant, 4HH cells (engineered by antisense knockdown of PAI-1 mRNA transcripts) resulted in marked cytostasis in the absence of NaB. The transfection of ras-transformed cells with the Rc/CMVPAI expression construct, moreover, significantly elevated constitutive PAI-1 synthesis (10- to 20-fold) with a concomitant reduction in proliferative rate. These data suggest that high-level PAI-1 expression suppresses growth of chronic ras-oncogene transformed cells and is likely a major cytostatic effector of NaB exposure.http://dx.doi.org/10.1155/2011/710974 |
| spellingShingle | Stephen P. Higgins Craig E. Higgins Paul J. Higgins PAI-1 Expression Is Required for HDACi-Induced Proliferative Arrest in ras-Transformed Renal Epithelial Cells International Journal of Cell Biology |
| title | PAI-1 Expression Is Required for HDACi-Induced Proliferative Arrest in ras-Transformed Renal Epithelial Cells |
| title_full | PAI-1 Expression Is Required for HDACi-Induced Proliferative Arrest in ras-Transformed Renal Epithelial Cells |
| title_fullStr | PAI-1 Expression Is Required for HDACi-Induced Proliferative Arrest in ras-Transformed Renal Epithelial Cells |
| title_full_unstemmed | PAI-1 Expression Is Required for HDACi-Induced Proliferative Arrest in ras-Transformed Renal Epithelial Cells |
| title_short | PAI-1 Expression Is Required for HDACi-Induced Proliferative Arrest in ras-Transformed Renal Epithelial Cells |
| title_sort | pai 1 expression is required for hdaci induced proliferative arrest in ras transformed renal epithelial cells |
| url | http://dx.doi.org/10.1155/2011/710974 |
| work_keys_str_mv | AT stephenphiggins pai1expressionisrequiredforhdaciinducedproliferativearrestinrastransformedrenalepithelialcells AT craigehiggins pai1expressionisrequiredforhdaciinducedproliferativearrestinrastransformedrenalepithelialcells AT pauljhiggins pai1expressionisrequiredforhdaciinducedproliferativearrestinrastransformedrenalepithelialcells |