Loss of protein kinase C function induces an apoptotic response

Whelan, Richard D. H.; Parker, Peter J.

doi:10.1038/sj.onc.1201725

Cited by 135 publications

(106 citation statements)

References 22 publications

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“…15 The apparent discrepancy between these studies and our current observation may be owing to the higher level of expression achieved by adenoviral-facilitated expression of PKCaKD (Matassa and Reyland, unpublished data). Importantly, our current findings are in line with studies from other investigators including Whelan and Parker, 17 who showed that loss of PKC function induced apoptosis in COS-1 and U937 cells. In addition, specific targeting of PKCa by antisense oligonucleotides or ribozymes blocks the growth of gliomas and increases apoptosis, 38,39 and inhibits the growth of lymphoma cells.…”

Section: Discussionsupporting

confidence: 82%

“…26 Depletion of PKCa induces apoptosis in glioblastoma multiforme cells 27 and in COS-7 cells. 17 Two studies have explored the molecular mechanism by which PKCa protects against apoptosis. Ruvolo et al 28 have shown that PKCa can phosphorylate Bcl-2 in vitro, and that overexpression of PKCa results in increased Bcl-2 phosphorylation and suppression of apoptosis in human pre-B REH cells.…”

Section: Introductionmentioning

confidence: 99%

“…[5][6][7] Serine/threonine protein kinases are also known to regulate apoptosis, including the phosphoinositide 3-kinase/AKT pathway, 8,9 members of the mitogen-activated protein kinase family (MAPKs), [10][11][12] and the protein kinase C (PKC) pathway. [13][14][15][16][17] The PKC family consists of 11 isoforms, with individual isoforms exhibiting varying substrate specificity, as well as differences in their subcellular localization and response to specific stimuli. 18,19 This argues that specific isoforms of PKC play unique roles in transducing cell signals.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of PKCα induces a PKCδ-dependent apoptotic program in salivary epithelial cells

et al. 2003

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We have used expression of a kinase dead mutant of PKCa (PKCaKD) to explore the role of this isoform in salivary epithelial cell apoptosis. Expression of PKCaKD by adenovirus-mediated transduction results in a dose-dependent induction of apoptosis in salivary epithelial cells as measured by the accumulation of sub-G1 DNA, activation of caspase-3, and cleavage of PKCd and PKCf, known caspase substrates. Induction of apoptosis is accompanied by ninefold activation of c-Jun-N-terminal kinase, and an approximately two to three-fold increase in activated mitogenactivated protein kinase (MAPK) as well as total MAPK protein. Previous studies from our laboratory have shown that PKCd activity is essential for the apoptotic response of salivary epithelial cells to a variety of cell toxins. To explore the contribution of PKCd to PKCaKD-induced apoptosis, salivary epithelial cells were cotransduced with PKCaKD and PKCdKD expression vectors. Inhibition of endogenous PKCd blocked the ability of PKCaKD to induce apoptosis as indicated by cell morphology, DNA fragmentation, and caspase-3 activation, indicating that PKCd activity is required for the apoptotic program induced under conditions where PKCa is inhibited. These findings indicate that PKCa functions as a survival factor in salivary epithelial cells, while PKCd functions to regulate entry into the apoptotic pathway.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibition of PKCα induces a PKCδ-dependent apoptotic program in salivary epithelial cells

et al. 2003

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“…Interestingly, the literature suggests that PKC-a has a predominantly antiapoptotic role (Deacon et al, 1997). For example, PKC-a is inhibited during ceramide-induced apoptosis (Lee et al, 1996) and expression of a dominant-negative PKC-a induced apoptosis in CHO cells (Whelan and Parker, 1998). Thus, those bile acids known to promote cell proliferation and inhibit butyrate-induced apoptosis, that is, UDCA, CDCA and DCA (Mahmoud et al, 1999;McMillan et al, 2000), are likely to be mediated by the activation of PKC-a.…”

Section: Discussionmentioning

confidence: 99%

Opposing effects of butyrate and bile acids on apoptosis of human colon adenoma cells: differential activation of PKC and MAP kinases

et al. 2003

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Butyrate, produced in the colon by fermentation of dietary fibre, induces apoptosis in colon adenoma and cancer cell lines, which may contribute to protection against colorectal cancer. However, butyrate is present in the colon along with other dietary factors, including unconjugated bile acids, which are tumour promoters. We have shown previously that the proapoptotic effects of butyrate on AA/C1 human adenoma cells were reduced in the presence of bile acids. To determine the cellular basis of this interaction, we examined the effects of butyrate and the secondary bile acid ursodeoxycholic acid (UDCA) on signalling pathways known to regulate apoptosis using AA/C1 cells. Butyrate activated PKC-d and p38 MAP (mitogen-activated protein) kinase, whereas UDCA activated PKC-a and p42/44 MAP kinase. Butyrate treatment also resulted in the caspase-3-mediated proteolysis of PKC-d. Butyrate-induced apoptosis was reduced by inhibitors of PKC-d (Rottlerin), p38 MAP kinase (SB202190) and caspase 3 (DEVD-fmk), whereas the proliferative/survival effects of UDCA were blocked by inhibitors of PKC-a (Gö 6976) and MEK 1 (PD98059). The effects of butyrate and bile acids are therefore mediated by the differential activation of signalling pathways that are known to regulate apoptosis.

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“…Down-regulation of PKC-␣ with anti-sense oligonucleotides leads to apoptosis of U937 cells. 270 PKC-␣ is capable of phosphorylating Bcl-2 at a site which increases its activity so it is likely that this is at least one mechanism by which PKC-␣ inhibits apoptosis. 271 PKC-␣ is clearly not the only factor that can prevent apoptosis in hematopoietic cells.…”

Section: Figurementioning

confidence: 99%

Kinases: positive and negative regulators of apoptosis

2000

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Cells sense and respond to extracellular factors via receptors on the cell surface that trigger intracellular signaling pathways. The signals received by the receptors on hematopoietic cells often determine if the cell proliferates, survives or undergoes apoptosis. Apoptosis can be induced by almost any cytotoxic stimuli. These stimuli may be an absence of signals arising from cellular receptors, stimulation of specific ligand receptors on the cell surface, chemotherapeutic agents, and ionizing radiation or oxygen radicals, as well as a number of other factors. Cellular kinases and phosphatases participate in signaling cascades that influence this process. We review the ability of the calmodulin-dependent-kinases, I-B kinases, PI3-kinases, Jakkinases, PKC, PKA, and MAP kinase signaling pathways (Erk, Jnk, and p38), to influence the apoptotic process. In addition, we discuss the cross-talk that exists between signaling cascades that are pro-apoptotic and anti-apoptotic.

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Loss of protein kinase C function induces an apoptotic response

Cited by 135 publications

References 22 publications

Inhibition of PKCα induces a PKCδ-dependent apoptotic program in salivary epithelial cells

Inhibition of PKCα induces a PKCδ-dependent apoptotic program in salivary epithelial cells

Opposing effects of butyrate and bile acids on apoptosis of human colon adenoma cells: differential activation of PKC and MAP kinases

Kinases: positive and negative regulators of apoptosis

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