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| Content Provider | PubMed Central |
|---|---|
| Author | Armand, Hornia Lu, Zhimin Sukezane, Taiko Zhong, Minghao Joseph, Troy Frankel, Paul Foster, David A. |
| Copyright Year | 1999 |
| Abstract | Downregulation of protein kinase C δ (PKC δ) by treatment with the tumor-promoting phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) transforms cells that overexpress the non-receptor class tyrosine kinase c-Src (Z. Lu et al., Mol. Cell. Biol. 17:3418–3428, 1997). We extended these studies to cells overexpressing a receptor class tyrosine kinase, the epidermal growth factor (EGF) receptor (EGFR cells); like c-Src, the EGF receptor is overexpressed in several human tumors. In contrast with expectations, downregulation of PKC isoforms with TPA did not transform the EGFR cells; however, treatment with EGF did transform these cells. Since TPA downregulates all phorbol ester-responsive PKC isoforms, we examined the effects of PKC δ- and PKC α-specific inhibitors and the expression of dominant negative mutants for both PKC δ and α. Consistent with a tumor-suppressing function for PKC δ, the PKC δ-specific inhibitor rottlerin and a dominant negative PKC δ mutant transformed the EGFR cells in the absence of EGF. In contrast, the PKC α-specific inhibitor Go6976 and expression of a dominant negative PKC α mutant blocked the transformed phenotype induced by both EGF and PKC δ inhibition. Interestingly, both rottlerin and EGF induced substantial increases in phospholipase D (PLD) activity, which is commonly elevated in response to mitogenic stimuli. The elevation of PLD activity in response to inhibiting PKC δ, like transformation, was dependent upon PKC α and restricted to the EGFR cells. These data demonstrate that PKC isoforms α and δ have antagonistic effects on both transformation and PLD activity and further support a tumor suppressor role for PKC δ that may be mediated by suppression of tyrosine kinase-dependent increases in PLD activity. |
| Starting Page | 7672 |
| File Format | |
| ISSN | 10985549 |
| e-ISSN | 10985549 |
| Journal | Molecular and Cellular Biology |
| Issue Number | 11 |
| Volume Number | 19 |
| Language | English |
| Publisher | American Society for Microbiology |
| Publisher Date | 1999-11-01 |
| Access Restriction | Open |
| Rights Holder | American Society for Microbiology |
| Subject Keyword | Research in Higher Education |
| Content Type | Text |
| Resource Type | Article |
| Subject | Cell Biology Molecular Biology |
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