Exacerbated vein graft arteriosclerosis in protein kinase Cδ–null mice

Leitges, Michael; Mayr, Manuel; Braun, Ursula; Mayr, Ursula; Li, Chaohong; Pfister, Gerald; Ghaffari-Tabrizi, Nassim; Baier, Gottfried; Hu, Yanhua; Xu, Qingbo

doi:10.1172/jci200112902

Cited by 219 publications

(146 citation statements)

References 39 publications

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“…PKC␦ regulates the interaction of Rad9 with Bcl-2 and the hRad9-mediated apoptotic response to DNA damage (10). Furthermore, previous studies showed that cells derivedfromPKC␦-nulltransgenicmiceweredefectiveinmitochondriadependent apoptosis (11). These findings collectively support a pivotal role for PKC␦ in the induction of apoptosis in response to DNA damage.…”

supporting

confidence: 72%

Protein Kinase C δ Regulates Ser46 Phosphorylation of p53 Tumor Suppressor in the Apoptotic Response to DNA Damage

Yoshida

Liu

Miki

2006

Journal of Biological Chemistry

166

133

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The p53 tumor suppressor is activated in the cellular response to genotoxic stress. Transactivation of p53 target genes dictates cell cycle arrest and DNA repair or induction of apoptosis; however, a molecular mechanism responsible for these distinct functions remains unclear. Recent studies revealed that phosphorylation of p53 on Ser 46 was associated with induction of p53AIP1 expression, resulting in the commitment of the cell fate into apoptotic cell death. Moreover, upon exposure to genotoxic stress, p53DINP1 was expressed and recruited a kinase(s) to p53 that specifically phosphorylated Ser 46 . Here, we show that the pro-apoptotic kinase, protein kinase C ␦ (PKC␦), is involved in phosphorylation of p53 on Ser 46 . PKC␦-mediated phosphorylation is required for the interaction of PKC␦ with p53. The results also demonstrate that p53DINP1 associates with PKC␦ upon exposure to genotoxic agents. Consistent with these results, PKC␦ potentiates p53-dependent apoptosis by Ser 46 phosphorylation in response to genotoxic stress. These findings indicate that PKC␦ regulates p53 to induce apoptotic cell death in the cellular response to DNA damage.The cellular response to genotoxic stress includes cell cycle arrest, activation of DNA repair and, in the event of irreparable damage, induction of apoptosis. The signaling mechanisms responsible for regulation of the DNA damage response are largely unclear. Certain insights have been derived from the finding that the ␦ isoform of protein kinase C (PKC) 2 is activated in response to DNA damage. Notably, PKC␦ is cleaved to a 40-kDa catalytically active fragment by caspase-3 in cells treated with DNA-damaging agents (1, 2). The finding that overexpression of the PKC␦ catalytic fragment (PKC␦CF) induces chromatin condensation and DNA fragmentation supports a role for PKC␦ cleavage in the induction of apoptotic cell death (3). Interaction of PKC␦CF with the nuclear DNA-dependent protein kinase catalytic subunit (DNAPKcs) inhibits the function of DNA-PKcs to form complexes with DNA and to phosphorylate its downstream target, p53 (4). In addition, cells deficient in DNA-PK are resistant to apoptosis induced by PKC␦CF overexpression (4). Other studies have shown that PKC␦ interacts with the c-Abl tyrosine kinase upon exposure to genotoxic stress (5). c-Abl is a pro-apoptotic tyrosine kinase that targets to the nucleus following genotoxic stress (6 -8). Importantly, c-Abl-mediated phosphorylation activates PKC␦ and induces translocation of PKC␦ to the nucleus (5). In concert with these findings, tyrosine phosphorylation of PKC␦ is necessary for its nuclear translocation and subsequent caspase-dependent cleavage in the apoptotic response to DNA damage (9). A recent study demonstrated that nuclear-targeted PKC␦ interacts with and phosphorylates a pro-apoptotic molecule, Rad9 (10). PKC␦ regulates the interaction of Rad9 with Bcl-2 and the hRad9-mediated apoptotic response to DNA damage (10). Furthermore, previous studies showed that cells derivedfromPKC␦-nulltransgenicmiceweredefective...

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supporting

confidence: 72%

Protein Kinase C δ Regulates Ser46 Phosphorylation of p53 Tumor Suppressor in the Apoptotic Response to DNA Damage

Yoshida

Liu

Miki

2006

Journal of Biological Chemistry

166

133

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“…TPA-induced PTP␣ and Src Activation Is Decreased in Fibroblasts from PKC␦ Knockout Mice-To further substantiate our findings, we set out to examine PTP␣ and Src activation after TPA treatment of cells that lack PKC␦ (22). Fibroblasts from PKC␦ knockout mice were prepared and compared with fibroblasts from wild-type mice.…”

Section: Fig 2 Ptp␣ Is Activated After Tpa Stimulationmentioning

confidence: 67%

“…Primary skin fibroblasts were isolated from newborn PKC␦Ϫ/Ϫ and PKC␦ϩ/ϩ mice from the same litter as described earlier (22) and cultured in the same way as A7r5 cells. Experiments were performed between passage 3-5.…”

mentioning

confidence: 99%

Protein Kinase Cδ Induces Src Kinase Activity via Activation of the Protein Tyrosine Phosphatase PTPα

Brandt

Goerke

Heuer

et al. 2003

Journal of Biological Chemistry

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Previously we have shown that protein kinase C (PKC)-mediated reorganization of the actin cytoskeleton in smooth muscle cells is transmitted by the nonreceptor tyrosine kinase, Src. Several authors have described how 12-O-tetradecanoylphorbol-13-acetate (TPA) stimulation of cells results in an increase of Src activity, but the mechanism of the PKC-mediated Src activation is unknown. Using PKC isozymes purified from Spodoptera frugiperda insect cells, we show here that PKC is not able to activate Src directly. Our data reveal that the PKC-dependent Src activation occurs via the activation of the protein tyrosine phosphatase (PTP) PTP␣. PTP␣ becomes activated in vivo after TPA stimulation. Further, we show that PKC␦ phosphorylates and activates only PTP␣ in vitro but not any other of the TPA-responsive PKC isozymes that are expressed in A7r5 rat aortic smooth muscle cells. To further substantiate our data, we show that cells lacking PKC␦ have a markedly reduced PTP␣ and Src activity after 12-O-tetradecanoylphorbol-13-acetate stimulation. These data support a model in which the main mechanism of 12-O-tetradecanoylphorbol-13-acetate-induced Src activation is the direct phosphorylation and activation of PTP␣ by PKC␦, which in turn dephosphorylates and activates Src.Protein kinase C (PKC) 1 is a family of phospholipid-dependent serine/threonine kinases comprising 10 isozymes differing in their molecular domain organization of up to 4 variable and 3 constant regions and in their functions. These PKC isozymes are subdivided into three classes: (i)the "conventional" cPKCs, PKC-␣, -␤ (␤I and ␤II), and -␥, which can be activated by phosphatidylserine (PS), diacyl glycerol (DAG), or phorbol esters through binding to the C1 domain and Ca 2ϩ through binding to a Ca 2ϩ -binding site in their second constant region, C2; (ii) the "novel" nPKCs, PKC-␦, -⑀, -, -, which lack the C2 region and thus are Ca-independent but still DAG-, PS-, and phorbol ester-responsive; and (iii) the "atypical" aPKCs, PKC-/ and -, which also lack the C2 region and, in addition, are devoid of a functional DAG-binding site. Hence, the atypical PKCs are only responsive to PS but not to DAG or phorbol ester (reviewed in Refs.

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“…11 When SMC apoptosis was altered as the result of gene deletions of p53 or protein kinase C ␦ (PKC␦), increased atherosclerotic lesions were seen in p53 Ϫ/Ϫ 12 and PKC␦ Ϫ/Ϫ mice. 13 Thus, mechanical stress-induced cell death is crucial in the development of atherosclerosis. 14,15 Integrins are cell surface receptors composed of ␣-and ␤-subunits.…”

mentioning

confidence: 99%

Mechanical Stretch-Induced Apoptosis in Smooth Muscle Cells Is Mediated by β ₁ -Integrin Signaling Pathways

Wernig

Mayr²,

Xu³

2003

Hypertension

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100

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Abstract-Recently we demonstrated that mechanical stress induces apoptosis of vascular smooth muscle cells in vitro and in vein grafts (Mayr et al. FASEB J. 2000;15:261-270). The current study was designed to investigate molecular mechanisms of mechanical stretch-induced apoptosis. Smooth muscle cells cultivated on silicone elastomer plates precoated with collagen I, elastin, laminin, or Pronectin were subjected to cyclic mechanical stretch. Interestingly, in response to mechanical stress, the number of apoptotic cells increased significantly in cells growing on collagen I-coated plates but not on other matrixes. We therefore thought that receptors mediating binding to collagen I, such as integrin ␤ 1 containing receptors, might be involved in signaling pathways leading to stretch-induced apoptosis. On collagen plates, mechanical stress rapidly activated p38 MAPK that phosphorylated p53 in smooth muscle cells. Lack of functional Rac completely abrogated p38 MAPK-p53 activation as well as apoptosis. Furthermore, mechanical stress resulted in increases of both integrin ␤ 1 protein expression and activity as identified by Western blotting and Shc immunoprecipitation assays. Treatment with a ␤ 1 -integrin-blocking antibody or integrin signaling inhibitor cytochalasin B but not growth factor receptor inhibitor suramin abrogated both stretch-induced phosphorylation of p38 MAPK and p53 expression. Akin to the inhibition of p38 MAPK-p53 signaling, pretreatment with a ␤ 1 -integrin-blocking antibody or cytochalasin B but not suramin inhibited stretch-induced apoptosis on collagen plates. These results suggest that mechanical stress-induced apoptosis in vascular smooth muscle cells is mediated by ␤ 1 -integrin-rac-p38-p53 signaling pathways.

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Exacerbated vein graft arteriosclerosis in protein kinase Cδ–null mice

Cited by 219 publications

References 39 publications

Protein Kinase C δ Regulates Ser46 Phosphorylation of p53 Tumor Suppressor in the Apoptotic Response to DNA Damage

Protein Kinase C δ Regulates Ser46 Phosphorylation of p53 Tumor Suppressor in the Apoptotic Response to DNA Damage

Protein Kinase Cδ Induces Src Kinase Activity via Activation of the Protein Tyrosine Phosphatase PTPα

Mechanical Stretch-Induced Apoptosis in Smooth Muscle Cells Is Mediated by β ₁ -Integrin Signaling Pathways

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Exacerbated vein graft arteriosclerosis in protein kinase Cδ–null mice

Cited by 219 publications

References 39 publications

Protein Kinase C δ Regulates Ser46 Phosphorylation of p53 Tumor Suppressor in the Apoptotic Response to DNA Damage

Protein Kinase C δ Regulates Ser46 Phosphorylation of p53 Tumor Suppressor in the Apoptotic Response to DNA Damage

Protein Kinase Cδ Induces Src Kinase Activity via Activation of the Protein Tyrosine Phosphatase PTPα

Mechanical Stretch-Induced Apoptosis in Smooth Muscle Cells Is Mediated by β 1 -Integrin Signaling Pathways

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Mechanical Stretch-Induced Apoptosis in Smooth Muscle Cells Is Mediated by β ₁ -Integrin Signaling Pathways