Triggering of a novel intrinsic apoptosis pathway by the kinase inhibitor staurosporine: activation of caspase‐9 in the absence of Apaf‐1

Manns, Joachim; Daubrawa, Merle; Drießen, Stefan; Paasch, Florian; Hoffmann, Nadine; Löffler, Antje S.; Lauber, Kirsten; Dieterle, Alexandra; Alers, Sebastian; Iftner, Thomas; Schulze‐Osthoff, Klaus; Stork, Björn; Wesselborg, Sebastian

doi:10.1096/fj.10-177527

Cited by 82 publications

(74 citation statements)

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“…The increased apoptosis appears to be at least partially p53 dependent (Figure 6b). Similar results were seen with the nongenotoxic agent staurosporine 36 ( Figure 6c and Supplementary Figure S7). TP8i cells also showed significantly higher activation of the executioner caspases 3/7 in response to both DOX and staurosporine in a p53+, but not p53i, background (Figure 6d).…”

Section: Resultssupporting

confidence: 83%

The novel p53 target TNFAIP8 variant 2 is increased in cancer and offsets p53-dependent tumor suppression

et al. 2016

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Tumor necrosis factor-α-induced protein 8 (TNFAIP8) is a stress-response gene that has been associated with cancer, but no studies have differentiated among or defined the regulation or function of any of its several recently described expression variants. We found that TNFAIP8 variant 2 (v2) is overexpressed in multiple human cancers, whereas other variants are commonly downregulated in cancer (v1) or minimally expressed in cancer or normal tissue (v3-v6). Silencing v2 in cancer cells induces p53-independent inhibition of DNA synthesis, widespread binding of p53, and induction of target genes and p53-dependent cell cycle arrest and DNA damage sensitization. Cell cycle arrest induced by v2 silencing requires p53-dependent induction of p21. In response to the chemotherapeutic agent doxorubicin, p53 regulates v2 through binding to an intragenic enhancer, together indicating that p53 and v2 engage in complex reciprocal regulation. We propose that TNFAIP8 v2 promotes human cancer by broadly repressing p53 function, in essence offsetting p53-dependent tumor suppression. Cell Death and Differentiation (2017) 24, 181-191; doi:10.1038/cdd.2016 published online 11 November 2016 Tumor necrosis factor-α-induced protein 8 (TNFAIP8) is the founding member of a recently described family of environmental stress response genes that are induced by TNFα. TNFAIP8 has been shown to promote or inhibit apoptosis, depending on cell type and context. 1,2 Although little is known about TNFAIP8, it has recently been found to be overexpressed in a wide range of human cancers. Some studies have suggested protumor functions for TNFAIP8, including enhancement of cell survival, proliferation, and metastasis [3][4][5][6][7][8][9] and resistance to cancer chemotherapeutics in mice. 4,10Nonetheless, nothing is known about how TNFAIP8 influences responses to DNA damage in cancer cells. Moreover, several transcript variants from the TNFAIP8 gene were recently registered in the NCBI reference sequence database, but no study to date has differentiated among them or defined the factors that govern their expression.The tumor suppressor p53 is a transcription factor that regulates many biological processes through its target gene network. Some of the well-characterized p53 target genes including p21/CDKN1A, growth arrest and DNA damageinducible 45a (GADD45A) and Bcl-2-like protein 4 (BAX) together promote senescence, cell cycle arrest, and apoptosis, all of which may contribute to the tumor suppressing functions of p53. 11,12Additional noncanonical tumorsuppressive pathways from p53 have recently been identified. [13][14][15] Improved characterization of the p53 DNAbinding sequence with modern sequencing techniques has led to the identification of a rapidly expanding list of p53 target genes. [16][17][18] Continued identification of these genes and characterization of their mechanisms of regulation and function will be critical to a full understanding of p53 and for full realization of opportunities to intervene upon p53 in cancer.Here, we identify ...

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Section: Resultssupporting

confidence: 83%

The novel p53 target TNFAIP8 variant 2 is increased in cancer and offsets p53-dependent tumor suppression

et al. 2016

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“…This cell specificity of the noncanonical intrinsic apoptotic pathway may explain the previous controversial results on staurosporine-induced cell death, which were obtained with different cell lines and tissues. 11,37,38 Fetal thymocytes that lacked the canonical mitochondrial apoptotic pathway, and the cell lines derived from them, efficiently underwent caspase-dependent apoptosis by staurosporine treatment, which agrees with the observation that many apoptotic cells are present in Apaf-1-null E14.5 fetal thymus.…”

Section: Discussionsupporting

confidence: 83%

“…On the other hand, Stepczynska et al 37 suggested that a mitochondrial-independent pathway was responsible for staurosporine-induced apoptosis because a dominantnegative Caspase-9 cannot inhibit it. Manns et al 38 recently claimed that a noncanonical staurosporine-induced apoptosis pathway requires Caspase-9 but not Apaf-1. In this report, we showed that staurosporine could activate caspase-dependent apoptosis via two different intrinsic pathways.…”

Section: Discussionmentioning

confidence: 99%

Apaf-1- and Caspase-8-independent apoptosis

Imao

Nagata²

2012

Cell Death Differ

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Two major apoptosis pathways, the mitochondrial and death receptor pathways, are well recognized. Here we established cell lines from the fetal thymus of Apaf-1-, Caspase-9-, or Bax/Bak-deficient mice. These cell lines were resistant to apoptosis induced by DNA-damaging agents, RNA or protein synthesis inhibitors, or stress in the endoplasmic reticulum. However, they underwent efficient apoptosis when treated with kinase inhibitors such as staurosporine and H-89, indicating that these inhibitors induce a caspase-dependent apoptosis that is different from the mitochondrial pathway. CrmA, a Caspase-8 inhibitor, did not prevent staurosporine-induced apoptosis of fetal thymic cell lines, suggesting that the death receptor pathway was also not involved in this process. The staurosporine-induced cell death was inhibited by okadaic acid, a serine/threonine phosphatase inhibitor, suggesting that dephosphorylation of a proapoptotic molecule triggered the death process, or that phosphorylation of an antiapoptotic molecule could block the process. Cells of various types (fetal thymocytes, bone marrows, thymocytes, and splenocytes), but not embryonic fibroblasts, were sensitive to the noncanonical staurosporine-induced apoptosis, suggesting that the noncanonical apoptosis pathway is tissue specific.

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“…In this study, we observed that AK-B knockdown in LCLs activated the internal apoptosis pathway through the activation of caspases 3 and 9. An internal apoptosis pathway activated via the cleavage of caspase 9 and 3 is well documented (74,75). Furthermore, previous studies also demonstrated that the mechanism behind caspase 3 activation and apoptosis (76)(77)(78) led to morphological and biochemical changes and the modification of key structural and regulatory proteins by caspase 3 (79,80).…”

Section: Discussionmentioning

confidence: 96%

EBNA3C-Mediated Regulation of Aurora Kinase B Contributes to Epstein-Barr Virus-Induced B-Cell Proliferation through Modulation of the Activities of the Retinoblastoma Protein and Apoptotic Caspases

Jha

Saha

et al. 2013

J Virol

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Epstein-Barr virus (EBV) is an oncogenic gammaherpesvirus that is implicated in several human malignancies, includingBurkitt's lymphoma (BL), posttransplant lymphoproliferative disease (PTLD), nasopharyngeal carcinoma (NPC), and AIDSassociated lymphomas. Epstein-Barr nuclear antigen 3C (EBNA3C), one of the essential EBV latent antigens, can induce mammalian cell cycle progression through its interaction with cell cycle regulators. Aurora kinase B (AK-B) is important for cell division, and deregulation of AK-B is associated with aneuploidy, incomplete mitotic exit, and cell death. Our present study shows that EBNA3C contributes to upregulation of AK-B transcript levels by enhancing the activity of its promoter. Further, EBNA3C also increased the stability of the AK-B protein, and the presence of EBNA3C leads to reduced ubiquitination of AK-B. Importantly, EBNA3C in association with wild-type AK-B but not with its kinase-dead mutant led to enhanced cell proliferation, and AK-B knockdown can induce nuclear blebbing and cell death. This phenomenon was rescued in the presence of EBNA3C. Knockdown of AK-B resulted in activation of caspase 3 and caspase 9, along with poly(ADP-ribose) polymerase 1 (PARP1) cleavage, which is known to be an important contributor to apoptotic signaling. Importantly, EBNA3C failed to stabilize the kinasedead mutant of AK-B compared to wild-type AK-B, which suggests a role for the kinase domain in AK-B stabilization and downstream phosphorylation of the cell cycle regulator retinoblastoma protein (Rb). This study demonstrates the functional relevance of AK-B kinase activity in EBNA3C-regulated B-cell proliferation and apoptosis.

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Triggering of a novel intrinsic apoptosis pathway by the kinase inhibitor staurosporine: activation of caspase‐9 in the absence of Apaf‐1

Cited by 82 publications

References 50 publications

The novel p53 target TNFAIP8 variant 2 is increased in cancer and offsets p53-dependent tumor suppression

The novel p53 target TNFAIP8 variant 2 is increased in cancer and offsets p53-dependent tumor suppression

Apaf-1- and Caspase-8-independent apoptosis

EBNA3C-Mediated Regulation of Aurora Kinase B Contributes to Epstein-Barr Virus-Induced B-Cell Proliferation through Modulation of the Activities of the Retinoblastoma Protein and Apoptotic Caspases

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