Caspase-8 sumoylation is associated with nuclear localization

Besnault-Mascard, Laurence; Leprince, Corinne; Auffredou, Marie Thérèse; Meunier, Brigitte; Bourgeade, Marie‐Françoise; Camonis, Jacques; Lorenzo, Hans K.; Vázquez, Aimé

doi:10.1038/sj.onc.1208448

Cited by 67 publications

(53 citation statements)

References 42 publications

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“…For example, sumoylation augments cell survival against hypoxia-or desferroxamine-induced injury by modulating adaptive responses in salivary epithelial cells (31). Although caspase-8 can be sumoylated at lysine156 and triggers its nuclear localization, it did not impair caspase-8 activation (32). Conceivably, sumoylation of antiapoptotic proteins can selectively protect them from proteolytic degradation, leading to an increment of cell survival.…”

Section: Discussionmentioning

confidence: 99%

Sumoylation of nucleophosmin/B23 regulates its subcellular localization, mediating cell proliferation and survival

Liu¹,

Liu²,

Jang³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Nucleophosmin/B23 is a major multifunctional nucleolar phosphoprotein that plays a critical role in ribosome biogenesis and cell proliferation. Arf tumor suppressor binds B23 and enhances its sumoylation. However, the biological effects of this event remain unknown. Here we show that B23 is sumoylated on both Lysine 230 and 263 residues, but the latter is the major one. Mutation of K263, but not K230, into R abolishes its centrosomal and nucleolar residency. Moreover, Rb binds to wild-type B23, but fails to interact with K263R. Sumoylation enhances B23 binding to Rb. Consequently, B23 potently stimulates E2F1-mediated transcriptional activity, which is abolished in B23 K263R. Further, K263R mutation makes B23 vulnerable to caspase-3 cleavage and sensitizes cells to apoptosis. Surprisingly, K230R mutant strongly binds to phosphatidylinositol-3,4,5-trisphosphate and suppresses DNA fragmentation. Thus, B23 sumoylation regulates its subcellular localization, cell proliferation, and survival activities.centrosome ͉ nucleolus ͉ sumoylation ͉ K263 N ucleophosmin (NPM)/B23 is a multifunctional protein involved in many cellular activities, and it has been attributed with both oncogenic and tumor-suppressive functions. B23 is more abundant in tumor and growing cells than in normal resting cells (1, 2). In addition, B23 is frequently found in the chromosomal translocation associated with several hematopoietic malignancies, such as acute promyelocytic leukemia (3), anaplastic large-cell lymphomas (4), and myelodysplasia/acute myeloid leukemia (5). Furthermore, certain mutations in the NPM gene incur the cytoplasmic localization of mutated B23, which has been proposed as a biomarker for certain acute myelogenous leukemia (6, 7). Overexpression of B23 induces cell cycle arrest in normal fibroblasts, whereas it promotes S phase entry in cells lacking p53. Conversely, knocking down B23 inhibits the processing of preribosomal RNA and induces cell death (8). In agreement with these observations, overexpression of B23 decreases the susceptibility of human leukemia HL-60 cells to retinoic acid-induced differentiation and apoptosis as well as UV-induced apoptosis in NIH 3T3 cells (9-11). Nonetheless, B23 can be cleaved by active caspase-3, which may influence its antiapoptotic action (12). It has been shown that B23 suppresses hypoxia or UV-induced cell death by repressing p53 phosphorylation and transcription activity (13,14). Recently, we presented biochemical evidence revealing that B23 is a nuclear phosphatidylinositol-3,4,5-trisphosphate [PI(3,4,5)P 3 ] receptor, and this complex directly interacts with caspase-activated DNase and inhibits its DNA fragmentation activity (15). Thus, these findings demonstrate that B23 acts as a physiologically important antiapoptotic protein. However, emerging evidence demonstrates that B23 can also act as a tumor suppressor. Npm germ-line deletion reveals that it is essential for embryonic development and the maintenance of genomic stability. Npm1 heterozygosity accelerates oncogenesis both in ...

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Section: Discussionmentioning

confidence: 99%

Sumoylation of nucleophosmin/B23 regulates its subcellular localization, mediating cell proliferation and survival

Liu¹,

Liu²,

Jang³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…15). Caspase-8 has a crucial role in macrophage differentiation (54) and has been specifically shown to undergo sumoylation at lysine 156 (55). Sumoylation of caspase-8 is associated with its nuclear localization while retaining its proteolytic activity (55), hence allowing the cleavage of endogenous and ectopic hnRNPs H1/H2 proteins in the nucleus of parental cells.…”

Section: Discussionmentioning

confidence: 99%

“…Caspase-8 has a crucial role in macrophage differentiation (54) and has been specifically shown to undergo sumoylation at lysine 156 (55). Sumoylation of caspase-8 is associated with its nuclear localization while retaining its proteolytic activity (55), hence allowing the cleavage of endogenous and ectopic hnRNPs H1/H2 proteins in the nucleus of parental cells. To verify that the degradation products are not a result of either the drug selection process after transfection or the electroporation procedure itself, we stably transfected parental U937 cells with a pcDNA harboring hnRNP G and evaluated the possible presence of its degradation products.…”

Section: Discussionmentioning

confidence: 99%

Heterogeneous Nuclear Ribonucleoprotein H1/H2-dependent Unsplicing of Thymidine Phosphorylase Results in Anticancer Drug Resistance

Stark¹,

Bram²,

Akerman

et al. 2011

Journal of Biological Chemistry

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Thymidine phosphorylase (TP) catalyzes the conversion of thymidine to thymine and 2-deoxyribose-1-phosphate. The latter plays an important role in induction of angiogenesis. As such, many human malignancies exhibit TP overexpression that correlates with increased microvessel density, formation of aggressive tumors, and dismal prognosis. Because TP is frequently overexpressed in cancer, pro-drugs were developed that utilize TP activity for their bioactivation to cytotoxic drugs. In this respect, TP is indispensable for the pharmacologic activity of the chemotherapeutic drug capecitabine, as it converts its intermediary metabolite 5-deoxyfluorouridine to 5-fluorouracil. Thus, loss of TP function confers resistance to the prodrug capecitabine, currently used for the treatment of metastatic colorectal cancer and breast cancer. However, drug resistance phenomena may frequently emerge that compromise the pharmacologic activity of capecitabine. Deciphering the molecular mechanisms underlying resistance to TP-activated prodrugs is an important goal toward the overcoming of such drug resistance phenomena. Here, we discovered that lack of TP protein in drug-resistant tumor cells is due to unsplicing of its pre-mRNA. Advanced bioinformatics identified the family of heterogeneous nuclear ribonucleoproteins (hnRNP) H/F as candidate splicing factors potentially responsible for impaired TP splicing. Indeed, whereas parental cells lacked nuclear localization of hnRNPs H1/H2 and F, drug-resistant cells harbored marked levels of these splicing factors. Nuclear RNA immunoprecipitation experiments established a strong binding of hnRNP H1/H2 to TP pre-mRNA, hence implicating them in TP splicing. Moreover, introduction of hnRNP H2 into drug-sensitive parental cells recapitulated aberrant TP splicing and 5-deoxyfluorouridine resistance. Thus, this is the first study identifying altered function of hnRNP H1/H2 in tumor cells as a novel determinant of aberrant TP splicing thereby resulting in acquired chemoresistance to TP-activated fluoropyrimidine anticancer drugs.

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“…The difference was that sumoylated caspase-8 seemed stable in ZD55-EGFP-infected cells, but gradually disappeared over time in ZD55-VEGI-251-infected cells. As poly(ADPribose) polymerase-2 (PARP-2) cleavage associates with the disappearance of the p75 form of caspase-8 in the nuclear fractions [21] and procaspase-3 is a substrate of active caspase-8 [22], enhanced PARP cleavage and procaspase-3 activation were observed in ZD55-VEGI-251-infected cells. Moreover, only ZD55-VEGI-251 can induce cleavage of caspase-9, suggesting the activation of mitochondria-mediated apoptosis signaling pathway.…”

Section: Zd55-vegi-251 Can Activate Mitochondria-mediated Apoptosis Smentioning

confidence: 99%

“…It is interesting to note that caspase-8 can be sumoylated after virus infection, which is associated with its nuclear localization [21]. The difference was that sumoylated caspase-8 seemed stable in ZD55-EGFP-infected cells, but gradually disappeared over time in ZD55-VEGI-251-infected cells.…”

Section: Zd55-vegi-251 Can Activate Mitochondria-mediated Apoptosis Smentioning

confidence: 99%

VEGI-armed oncolytic adenovirus inhibits tumor neovascularization and directly induces mitochondria-mediated cancer cell apoptosis

et al. 2009

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Vascular endothelial cell growth inhibitor (VEGI) is a member of the tumor necrosis factor superfamily and plays an important role in vascular homeostasis. In this study, to investigate the anticancer therapeutic potential of this gene, a secreted isoform of VEGI (VEGI-251) was inserted into a selectively replicating adenovirus with E1B 55 kDa gene deletion (ZD55) to construct ZD55-VEGI-251. We report here that secreted VEGI-251 produced from ZD55-VEGI-251-infected cancer cells potently inhibits endothelial cell proliferation, tube formation in vitro and angiogenesis of chick chorioallantoic membrane in vivo. Additionally, ZD55-VEGI-251 infection leads to a much more severe cytopathic effect than control viruses on several human cancer cell lines, including cervical cancer cell line HeLa, hepatoma cell line SMMC-7721 and colorectal cancer cell line SW620. Further study reveals that the increased cytotoxicity is a result of VEGI-251 autocrine-dependent, mitochondria-mediated apoptosis accompanied by caspase-9 activation, enhanced caspase-3 activation and PARP cleavage. Moreover, ZD55-VEGI-251-treatment of athymic nude mice bearing human cervical and colorectal tumor xenografts markedly suppressed tumor growth. Our findings indicate that the combined effect of antiangiogenesis and apoptosis-induction activity makes the VEGI-251-armed oncolytic adenovirus a promising therapeutic agent for cancer.

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Caspase-8 sumoylation is associated with nuclear localization

Cited by 67 publications

References 42 publications

Sumoylation of nucleophosmin/B23 regulates its subcellular localization, mediating cell proliferation and survival

Sumoylation of nucleophosmin/B23 regulates its subcellular localization, mediating cell proliferation and survival

Heterogeneous Nuclear Ribonucleoprotein H1/H2-dependent Unsplicing of Thymidine Phosphorylase Results in Anticancer Drug Resistance

VEGI-armed oncolytic adenovirus inhibits tumor neovascularization and directly induces mitochondria-mediated cancer cell apoptosis

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