Overexpression of Protein Kinase C δ Represses Expression of Proliferin in NIH3T3 Cells That Regulates Cell Proliferation

Kang, Yup; Park, Jae Sook; Kim, Sung Hye; Shin, Yoo Jung; Kim, Wankee; Joo, Hee-Jae; Chun, Jang‐Soo; Kim, Hyon Ju; Ha, Mahn Joon

doi:10.1006/mcbr.2001.0276

Cited by 11 publications

(9 citation statements)

References 22 publications

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“…These results support the concept that PKC-␦ could mediate the M-CSF-induced growthinhibitory signal at least partially. In support of this, PKC-␦ has been implicated in the negative regulation of cell division, also in other cell types such as fibroblasts and B cells [19,42].…”

Section: Discussionmentioning

confidence: 81%

M-CSF induced differentiation of myeloid precursor cells involves activation of PKC-δ and expression of Pkare

Junttila

Bourette

Rohrschneider

et al. 2003

Journal of Leukocyte Biology

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Macrophage-colony stimulating factor (M-CSF) regulates proliferation and differentiation of cells belonging to the monocytic lineage. We investigated the mechanisms of M-CSF differentiation signaling in follicular dendritic cell-P1 cells and analyzed the catalytic activation of different protein kinase C (PKC) isoforms. M-CSF induced rapid catalytic activation of PKC-delta and membrane translocation of the tyrosine phosphorylated form of PKC-delta. Mutation of tyrosine 807 in the M-CSF receptor (Fms) abrogates cell differentiation but not a proliferative response to M-CSF, and FmsY807F failed to activate PKC-delta. We also investigated the downstream signaling pathways from PKC-delta. A cyclic adenosine monophosphate-regulated Ser/Thr kinase gene, protein kinase X (PRKX), has been associated with macrophage differentiation in human cells. We found that M-CSF and PKC-delta induced the expression of the PRKX murine homologue: PKA-related gene. Taken together, our results indicate that PKC-delta functions as a critical mediator of M-CSF-induced differentiation signaling.

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Section: Discussionmentioning

confidence: 81%

M-CSF induced differentiation of myeloid precursor cells involves activation of PKC-δ and expression of Pkare

Junttila

Bourette

Rohrschneider

et al. 2003

Journal of Leukocyte Biology

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“…These results unequivocally point to PKC-d having a specific action in the execution of Aplidin TM -mediated cytotoxicity. Different roles for PKC-d activity during apoptosis have been reported, such as disassembly of nuclear lamina (Cross et al, 2000), inhibition of proliferin expression (Kang et al, 2000) and inactivation of DNA protein kinase (Bharti et al, 1998) among others (Gschwendt, 1999 and references therein). In addition, it has been reported that PKC-d activates the MEK-ERK pathway (Ueda et al, 1996), which could explain the delayed ERK phosphorylation observed during the Aplidin TM -induced apoptotic process, that coincides in time with the proteolytic activation of PKC-d.…”

Section: Discussionmentioning

confidence: 99%

Aplidin™ induces the mitochondrial apoptotic pathway via oxidative stress-mediated JNK and p38 activation and protein kinase C δ

et al. 2002

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AplidinTM , a new antitumoural drug presently in phase II clinical trials, has shown both in vitro and in vivo activity against human cancer cells. Aplidin TM effectively inhibits cell viability by triggering a canonical apoptotic program resulting in alterations in cell morphology, caspase activation, and chromatin fragmentation. Pro-apoptotic concentrations of Aplidin TM induce early oxidative stress, which results in a rapid and persistent activation of both JNK and p38 MAPK and a biphasic activation of ERK. Inhibition of JNK and p38 MAPK blocks the apoptotic program induced by Aplidin TM , demonstrating its central role in the integration of the cellular stress induced by the drug. JNK and p38 MAPK activation results in downstream cytochrome c release and activation of caspases -9 and -3 and PARP cleavage, demonstrating the mediation of the mitochondrial apoptotic pathway in this process. We also demonstrate that protein kinase C delta (PKC-d) mediates the cytotoxic effect of Aplidin TM and that it is concomitantly processed and activated late in the apoptotic process by a caspase mediated mechanism. Remarkably, cells deficient in PKC-d show enhanced survival upon drug treatment as compared to its wild type counterpart. PKC-d thus appears as an important component necessary for full caspase cascade activation and execution of apoptosis, which most probably initiates a positive feedback loop further amplifying the apoptotic process.

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“…Moreover, since PKCd has been described as growth inhibitory in a large number of cell types, it was proposed that this kinase should be the main effector of AD 198 cytotoxicity [10]. In this sense, NIH3T3 cells overexpressing PKCd have shown an important reduction in their proliferation rate [11,12]. This effect has also been reported in other cell types, including glial [13], endothelial [14], and breast cancer [15] cells.…”

Section: Introductionmentioning

confidence: 98%

Involvement of PKC delta (PKCδ) in the resistance against different doxorubicin analogs

Bessone

Berardi

Campodónico

et al. 2010

Breast Cancer Res Treat

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Doxorubicin is an anti-tumor antibiotic widely used in the management of cancer patients. Its main mechanism of action involves the generation of DNA damage and the inhibition of topoisomerase II, promoting apoptosis. AD 198 is a novel doxorubicin analog devoid of DNA binding and topoisomerase II inhibitory capacities. It has been proposed that AD 198 induces apoptosis by activating protein kinase C delta (PKCδ); a PKC isoform described as growth inhibitory in a large number of cell types. We have previously demonstrated that PKCδ overexpression in NMuMG cells induced the opposite effect, promoting proliferation and cell survival. In this study, we found that PKCδ overexpression confers an enhanced cell death resistance against AD 198 cytotoxic effect and against AD 288, another doxorubicin analog that preserves its mechanism of action. These resistances involve PKCδ-mediated activation of two well-known survival pathways: Akt and NF-κB. While the resistance against AD 198 could be abrogated upon the inhibition of either Akt or NF-κB pathways, only NF-κB inhibition could revert the resistance to AD 288. Altogether, our results indicate that PKCδ increases cell death resistance against different apoptosis inductors, independently of their mechanism of action, through a differential modulation of Akt and NF-κB pathways. Our study contributes to a better understanding of the mechanisms involved in PKCδ-induced resistance and may greatly impact in the rationale design of isozyme-specific PKC modulators as therapeutic agents.

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Overexpression of Protein Kinase C δ Represses Expression of Proliferin in NIH3T3 Cells That Regulates Cell Proliferation

Cited by 11 publications

References 22 publications

M-CSF induced differentiation of myeloid precursor cells involves activation of PKC-δ and expression of Pkare

M-CSF induced differentiation of myeloid precursor cells involves activation of PKC-δ and expression of Pkare

Aplidin™ induces the mitochondrial apoptotic pathway via oxidative stress-mediated JNK and p38 activation and protein kinase C δ

Involvement of PKC delta (PKCδ) in the resistance against different doxorubicin analogs

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