| 1. |
- Cornmark, Louise, et al.
(author)
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Protein kinase Cα suppresses the expression of STC1 in MDA-MB-231 breast cancer cells
- 2011
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In: Tumour Biology. - : Springer Science and Business Media LLC. - 1423-0380 .- 1010-4283. ; 32:5, s. 1023-1030
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Journal article (peer-reviewed)abstract
- Several protein kinase C (PKC) isoforms have been shown to influence different cellular processes that may contribute to the malignancy of breast cancer cells. To obtain insight into mechanisms mediating the PKC effects, global gene expression was analyzed in MDA-MB-231 breast cancer cells in which PKCα, PKCδ or PKCε had been down-regulated with siRNA. Gene set enrichment analyses revealed that hypoxia-induced genes were enriched among genes that increased in PKCα-down-regulated cells. The STC1 mRNA, encoding stanniocalcin 1, was particularly up-regulated following depletion of PKCα and was also induced by hypoxia. Both hypoxia and PKCα down-regulation also led to increased STC1 protein levels. The results demonstrate that PKCα suppresses the expression of STC1 in breast cancer cells
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| 2. |
- Holmgren, Christian, et al.
(author)
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Molecular characterization of protein kinase C delta (PKCδ)-Smac interactions
- 2016
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In: BMC Biochemistry. - : Springer Science and Business Media LLC. - 1471-2091. ; 17:1
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Journal article (peer-reviewed)abstract
- Background: Protein kinase C o (PKCo) is known to be an important regulator of apoptosis, having mainly pro-but also anti-Apoptotic effects depending on context. In a previous study, we found that PKCo interacts with the pro-Apoptotic protein Smac. Smac facilitates apoptosis by suppressing inhibitor of apoptosis proteins (IAPs). We previously established that the PKCo-Smac complex dissociates during induction of apoptosis indicating a functional importance. Because the knowledge on the molecular determinants of the interaction is limited, we aimed at characterizing the interactions between PKCo and Smac. Results: We found that PKCo binds directly to Smac through its regulatory domain. The interaction is enhanced by the PKC activator TPA and seems to be independent of PKCo catalytic activity since the PKC kinase inhibitor GF109203X did not inhibit the interaction. In addition, we found that C1 and C2 domains from several PKC isoforms have Smac-binding capacity. Conclusions: Our data demonstrate that the Smac-PKCo interaction is direct and that it is facilitated by an open conformation of PKCo. The binding is mediated via the PKCo regulatory domain and both the C1 and C2 domains have Smac-binding capacity. With this study we thereby provide molecular information on an interaction between two apoptosis-regulating proteins.
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| 3. |
- Kalstad Lönne, Gry, et al.
(author)
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PKCalpha expression is a marker for breast cancer aggressiveness.
- 2010
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In: Molecular cancer. - : Springer Science and Business Media LLC. - 1476-4598. ; 9
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Journal article (peer-reviewed)abstract
- Protein kinase C (PKC) isoforms are potential targets for breast cancer therapy. This study was designed to evaluate which PKC isoforms might be optimal targets for different breast cancer subtypes.
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| 4. |
- Kalstad Lönne, Gry
(author)
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Protein Kinase C as an Apoptosis Regulator and a Potential Prognostic Factor in Breast Cancer
- 2010
-
Doctoral thesis (other academic/artistic)abstract
- Several protein kinase C (PKC) isoforms have been suggested as potential targets for breast cancer therapy. To explore the role for PKC isoforms in processes that facilitates malignant progression and the utility of PKC isoforms as biomarkers in breast cancer, we designed a study where we evaluated the expression of PKCα, δ, and ε in primary breast cancers as well as in breast cancer cell lines. We found that PKCα levels correlated to estrogen and progesterone receptor negativity, tumor grade, and proliferative activity, whereas PKCδ and PKCε did not correlate to clinicopathological parameters. Moreover, patients with PKCα-positive tumors showed poorer survival than patients with PKCα-negative tumors independently of other factors. We also observed that PKCα favored proliferation and migration in cultured breast cancer cells. Since mechanisms that mediate apoptosis resistance are attractive therapeutic targets for cancer, we also investigated the involvement of PKC isoforms in survival and apoptosis of breast cancer cells. PKCδ is considered a pro-apoptotic factor in many cell types. In breast cancer, however, it has shown both pro-survival and pro-apoptotic effects. We have found that down-regulation of PKCδ per se leads to apoptosis of MDA-MB-231 cells, a breast cancer cell lines with constitutive activation of the ERK1/2 pathway due to activation mutations of Ras and Raf. The apoptosis induced by PKCδ silencing was found to be accompanied by further increased MEK1/2 and ERK1/2 phosphorylation as well as reduced levels of the ERK1/2 phosphatase MKP3. These results suggest that PKCδ favors survival by suppressing the ERK1/2 pathway upstream and downstream of ERK1/2. We also show that PKCδ is involved in other aspect of apoptosis regulation since it interacts with Smac in breast cancer cells. The interaction is mediated via the C1b domain in the regulatory domain of PKCδ and depends on the N-terminus of Smac. Treatment with lethal triggers, such as paclitaxel, causes dissociation of the interaction, which is accompanied with release of Smac from the mitochondria. Activation of PKC by phorbol esters rescues the interaction during paclitaxel exposure concomitant with a suppression of cell death. Taken together, we have identified a previously unrecognized interaction and suggest that the PKCδ-Smac association may prevent apoptotic effects of Smac and protect it from degradation.
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| 5. |
- Kalstad Lönne, Gry, et al.
(author)
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Protein kinase Cdelta supports survival of MDA-MB-231 breast cancer cells by suppressing the ERK1/2 pathway
- 2009
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In: Journal of Biological Chemistry. - : The American Society for Biochemistry and Molecular Biology, Inc.. - 0021-9258 .- 1083-351X. ; 284:48, s. 33456-33465
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Journal article (peer-reviewed)abstract
- Mechanisms that mediate apoptosis resistance are attractive therapeutic targets for cancer. Protein kinase Cdelta (PKCdelta) is considered a pro-apoptotic factor in many cell types. In breast cancer, however, it has shown both pro-survival and pro-apoptotic effects. Here, we report for the first time that down-regulation of PKCdelta per se leads to apoptosis of MDA-MB-231 cells. Inhibition of MEK1/2 by either PD98059 or U0126 suppressed the induction of apoptosis of PKCdelta-depleted MDA-MB-231 cells but did not support survival of MCF-7 or MDA-MB-468 cells. Basal ERK1/2 phosphorylation was substantially higher in MDA-MB-231 cells than in the other cell lines. PKCdelta depletion led to even higher ERK1/2 phosphorylation levels and also to lower expression levels of the ERK1/2 phosphatase MKP3. Depletion of MKP3 led to apoptosis and higher levels of ERK1/2 phosphorylation, suggesting that this may be a mechanism mediating the effect of PKCdelta down-regulation. However, PKCdelta silencing also induced increased MEK1/2 phosphorylation, indicating that PKCdelta regulates ERK1/2 phosphorylation both upstream and downstream. Moreover, PKCdelta silencing led to increased levels of the E3 ubiquitin ligase Nedd4, which is a potential regulator of MKP3, because down-regulation led to increased MKP3 levels. Our results highlight PKCdelta as a potential target for therapy of breast cancers with high activity of the ERK1/2 pathway.
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| 6. |
- Masoumi, Katarzyna, et al.
(author)
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Identification of a novel protein kinase Cδ-Smac complex that dissociates during paclitaxel-induced cell death.
- 2012
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In: FEBS Letters. - : Wiley. - 1873-3468 .- 0014-5793. ; 586:8, s. 1166-1172
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Journal article (peer-reviewed)abstract
- Protein kinase C (PKC) δ is a regulator of apoptosis with both pro- and anti-apoptotic effects. The mechanistic basis for the discrepant effects is not completely understood. Here we show that Smac interacts with PKCδ. The interaction depends on the N-terminus of Smac and is disrupted upon treatment with paclitaxel. This is associated with release of Smac into the cytosol. Activation of PKCδ rescues the interaction during paclitaxel exposure and suppresses the paclitaxel-mediated cell death. However, under these conditions the complex is mainly found in the cytosol suggesting that cytosolic Smac can be bound by PKCδ when PKC is activated. The data unravel a previously unrecognized interaction and suggest that PKCδ by associating with Smac may prevent its apoptotic effects. STRUCTURED SUMMARY OF PROTEIN INTERACTIONS: PKC deltaphysically interacts with SMAC by anti bait coimmunoprecipitation (View Interaction: 1, 2, 3, 4) XIAPphysically interacts with SMAC by anti tag coimmunoprecipitation(View interaction).
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