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  • 1
    Online Resource
    Online Resource
    A Pharmacologic Inhibitor of the Protease Taspase1 Effectively Inhibits Breast and Brain Tumor Growth
    American Association for Cancer Research (AACR) ; 2012
    In:  Cancer Research Vol. 72, No. 3 ( 2012-02-01), p. 736-746
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 72, No. 3 ( 2012-02-01), p. 736-746
    Abstract: The threonine endopeptidase Taspase1 has a critical role in cancer cell proliferation and apoptosis. In this study, we developed and evaluated small molecule inhibitors of Taspase1 as a new candidate class of therapeutic modalities. Genetic deletion of Taspase1 in the mouse produced no overt deficiencies, suggesting the possibility of a wide therapeutic index for use of Taspase1 inhibitors in cancers. We defined the peptidyl motifs recognized by Taspase1 and conducted a cell-based dual-fluorescent proteolytic screen of the National Cancer Institute diversity library to identify Taspase1 inhibitors (TASPIN). On the basis of secondary and tertiary screens the 4-[(4-arsonophenyl)methyl]phenyl] arsonic acid NSC48300 was determined to be the most specific active compound. Structure–activity relationship studies indicated a crucial role for the arsenic acid moiety in mediating Taspase1 inhibition. Additional fluorescence resonance energy transfer–based kinetic analysis characterized NSC48300 as a reversible, noncompetitive inhibitor of Taspase1 (Ki = 4.22 μmol/L). In the MMTV-neu mouse model of breast cancer and the U251 xenograft model of brain cancer, NSC48300 produced effective tumor growth inhibition. Our results offer an initial preclinical proof-of-concept to develop TASPINs for cancer therapy. Cancer Res; 72(3); 736–46. ©2011 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-11-2584
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 2
    Online Resource
    Online Resource
    Taspase1 Functions as a Non-Oncogene Addiction Protease that Coordinates Cancer Cell Proliferation and Apoptosis
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Research Vol. 70, No. 13 ( 2010-07-01), p. 5358-5367
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 13 ( 2010-07-01), p. 5358-5367
    Abstract: Taspase1, the mixed lineage leukemia and TFIIAα-β cleaving protease, enables cell proliferation and permits oncogenic initiation. Here, we show its critical role in cancer maintenance and thus offer a new anticancer target. Taspase1 is overexpressed in primary human cancers, and deficiency of Taspase1 in cancer cells not only disrupts proliferation but also enhances apoptosis. Mechanistically, loss of Taspase1 induces the levels of CDK inhibitors (CDKI: p16, p21, and p27) and reduces the level of antiapoptotic MCL-1. Therapeutically, deficiency of Taspase1 synergizes with chemotherapeutic agents and ABT-737, an inhibitor of BCL-2/BCL-XL, to kill cancer cells. Taspase1 alone or in conjunction with MYC, RAS, or E1A fails to transform NIH/3T3 cells or primary mouse embryonic fibroblasts, respectively, but plays critical roles in cancer initiation and maintenance. Therefore, Taspase1 is better classified as a “non-oncogene addiction” protease, the inhibition of which may offer a novel anticancer therapeutic strategy. The reliance of oncogenes on subordinate non-oncogenes during tumorigenesis underscores the non-oncogene addiction hypothesis in which a large class of non-oncogenes functions to maintain cancer phenotypes and presents attractive anticancer therapeutic targets. The emergence of successful cancer therapeutics targeting non-oncogenes to which cancers are addicted supports the future development and potential application of small-molecule Taspase1 inhibitors for cancer therapy. Cancer Res; 70(13); 5358–67. ©2010 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-10-0027
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 3
    Online Resource
    Online Resource
    The Role of MLL in DNA Damage Checkpoint and Its Implication in Leukemogenesis
    American Society of Hematology ; 2008
    In:  Blood Vol. 112, No. 11 ( 2008-11-16), p. 5332-5332
    Details
    In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 5332-5332
    Abstract: Cell cycle checkpoints are implemented to safeguard our genome and the deregulation of which results in human cancers. Hence, it is of great significance to discover and investigate novel key constituents of the mammalian DNA damage response network. Human chromosome band 11q23 translocation disrupting the MLL gene leads to poor prognostic leukemias. MLL is a transcription co-activator that maintains HOX gene expression. The importance of HOX gene deregulation in MLL leukemogenesis has been intensively investigated. However, physiological murine MLL leukemia knockin models have indicated that incurred HOX gene aberration alone is insufficient to initiate MLL leukemia. Thus, additional signaling pathway must be involved, which remains to be discovered. Our recent studies demonstrated an intimate relationship between MLL and the cell cycle(Takeda et al. 2006, Genes & Development, 20, 2397–2409; Liu et al. 2007, Genes & Development, 21, 2385–2398). More importantly, our studies uncovered a critical role of MLL in executing the S phase checkpoint. We showed: Over-expression of MLL induces an S phase block. MLL accumulates in the S phase upon DNA damage. MLL deficiency results in radioresistant DNA synthesis (RDS) and chromatid-type chromosomal abnormalities, two signature characteristics of S phase checkpoint defects. We further determined the underlying mechanisms concerning the DNA damage-induced MLL accumulation. Our data showed that MLL is phosphorylated after DNA damage, which in turn blocks its degradation by SCFSkp2 in the S phase and results in the ultimate accumulation. Our data revealed the link between MLL and the S phase checkpoint, which provides novel insights into the mammalian cell cycle checkpoint network and human leukemia pathogenesis. Future studies utilizing murine leukemia models will be performed to examine whether MLL translocation compromises the S phase checkpoint and if the resulted dysfunction contributes to MLL leukemogenesis.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V112.11.5332.5332
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2008
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
    Online Resource
    Online Resource
    BAX activation is initiated at a novel interaction site
    Springer Science and Business Media LLC ; 2008
    In:  Nature Vol. 455, No. 7216 ( 2008-10), p. 1076-1081
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 455, No. 7216 ( 2008-10), p. 1076-1081
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/nature07396
    RVK:
    TA 1000
    RVK:
    UA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2008
    detail.hit.zdb_id: 120714-3
    detail.hit.zdb_id: 1413423-8
    SSG: 11
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  • 5
    Online Resource
    Online Resource
    Bax-independent inhibition of apoptosis by Bcl-XL
    Springer Science and Business Media LLC ; 1996
    In:  Nature Vol. 379, No. 6565 ( 1996-2), p. 554-556
    Details
    In: Nature, Springer Science and Business Media LLC, Vol. 379, No. 6565 ( 1996-2), p. 554-556
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
    URL: Article
    DOI: 10.1038/379554a0
    RVK:
    TA 1000
    RVK:
    UA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 1996
    detail.hit.zdb_id: 120714-3
    detail.hit.zdb_id: 1413423-8
    SSG: 11
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    Online Resource
  • 6
    Online Resource
    Online Resource
    Proteolysis of MLL family proteins is essential for Taspase1-orchestrated cell cycle progression
    Cold Spring Harbor Laboratory ; 2006
    In:  Genes & Development Vol. 20, No. 17 ( 2006-09-01), p. 2397-2409
    Details
    In: Genes & Development, Cold Spring Harbor Laboratory, Vol. 20, No. 17 ( 2006-09-01), p. 2397-2409
    Abstract: Taspase1 was identified as the threonine endopeptidase that cleaves mixed-lineage leukemia (MLL) for proper Hox gene expression in vitro. To investigate its functions in vivo, we generated Taspase1 −/− mice. Taspase1 deficiency results in noncleavage (nc) of MLL and MLL2 and homeotic transformations. Remarkably, our in vivo studies uncover an unexpected role of Taspase1 in the cell cycle. Taspase1 −/− animals are smaller in size. Taspase1 −/− mouse embryonic fibroblasts (MEFs) exhibit impaired proliferation, and acute deletion of Taspase1 leads to a marked reduction of thymocytes. Taspase1 deficiency incurs down-regulation of Cyclin Es , As , and Bs and up-regulation of p16 Ink4a . We show that MLL and MLL2 directly target E2Fs for Cyclin expression. The uncleaved precursor MLL displays a reduced histone H3 methyl transferase activity in vitro. Accordingly, chromatin immunoprecipitation assays demonstrate a markedly decreased histone H3 K4 trimethylation at Cyclin E1 and E2 genes in Taspase1 −/− cells. Furthermore, MLL nc/nc;2nc/nc MEFs are also impaired in proliferation. Our data are consistent with a model in which precursor MLLs, activated by Taspase1, target to Cyclins through E2Fs to methylate histone H3 at K4, leading to activation. Lastly, Taspase1 −/− cells are resistant to oncogenic transformation, and Taspase1 is overexpressed in many cancer cell lines. Thus, Taspase1 may serve as a target for cancer therapeutics.
    Type of Medium: Online Resource
    ISSN: 0890-9369 , 1549-5477
    URL: Article
    DOI: 10.1101/gad.1449406
    RVK:
    WA 15000
    Language: English
    Publisher: Cold Spring Harbor Laboratory
    Publication Date: 2006
    detail.hit.zdb_id: 1467414-2
    SSG: 12
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  • 7
    Online Resource
    Online Resource
    The p53-cathepsin axis cooperates with ROS to activate programmed necrotic death upon DNA damage
    Proceedings of the National Academy of Sciences ; 2009
    In:  Proceedings of the National Academy of Sciences Vol. 106, No. 4 ( 2009-01-27), p. 1093-1098
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 106, No. 4 ( 2009-01-27), p. 1093-1098
    Abstract: Three forms of cell death have been described: apoptosis, autophagic cell death, and necrosis. Although genetic and biochemical studies have formulated a detailed blueprint concerning the apoptotic network, necrosis is generally perceived as a passive cellular demise resulted from unmanageable physical damages. Here, we conclude an active de novo genetic program underlying DNA damage-induced necrosis, thus assigning necrotic cell death as a form of “programmed cell death.” Cells deficient of the essential mitochondrial apoptotic effectors, BAX and BAK, ultimately succumbed to DNA damage, exhibiting signature necrotic characteristics. Importantly, this genotoxic stress-triggered necrosis was abrogated when either transcription or translation was inhibited. We pinpointed the p53-cathepsin axis as the quintessential framework underlying necrotic cell death. p53 induces cathepsin Q that cooperates with reactive oxygen species (ROS) to execute necrosis. Moreover, we presented the in vivo evidence of p53-activated necrosis in tumor allografts. Current study lays the foundation for future experimental and therapeutic discoveries aimed at “programmed necrotic death.”
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0808173106
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2009
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 8
    Online Resource
    Online Resource
    Anti-apoptotic bcl-2 homologs encoded by Kaposi's sarcoma-associated virus and herpesvirus saimiri; a role during virus infections : 83
    Ovid Technologies (Wolters Kluwer Health) ; 1997
    In:  Journal of Acquired Immune Deficiency Syndromes & Human Retrovirology Vol. 14, No. 4 ( 1997-04), p. A37-
    Details
    In: Journal of Acquired Immune Deficiency Syndromes & Human Retrovirology, Ovid Technologies (Wolters Kluwer Health), Vol. 14, No. 4 ( 1997-04), p. A37-
    Type of Medium: Online Resource
    ISSN: 1077-9450
    URL: Article
    DOI: 10.1097/00042560-199704010-00124
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 1997
    detail.hit.zdb_id: 2038673-4
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  • 9
    Online Resource
    Online Resource
    Proapoptotic BAX and BAK control multiple initiator caspases
    EMBO ; 2005
    In:  EMBO reports Vol. 6, No. 4 ( 2005-04), p. 379-385
    Details
    In: EMBO reports, EMBO, Vol. 6, No. 4 ( 2005-04), p. 379-385
    Abstract: BAX and BAK operate at both the mitochondria and endoplasmic reticulum (ER) to regulate the intrinsic apoptotic pathway. An unresolved issue is whether any caspases can be activated in response to intrinsic apoptotic signals in the absence of BAX and BAK. Following organelle‐specific intrinsic stress signals, including DNA damage and ER stress, we detected no activation of CARD‐containing caspases (initiator CASP)‐1, ‐2, ‐9, ‐11 and ‐12 in Bax −/− Bak −/− doubly deficient (DKO) cells. BCL‐2 overexpression in these DKO cells provided no further protection to their already strong protection from DNA damage and ER stress. Moreover, there was no activation of effector CASP‐3 and ‐7 in DKO cells, consistent with the lack of initiator caspase activity and disfavouring a BAX, BAK‐independent intrinsic apoptotic pathway to activate initiator caspases. Thus, BAX and BAK confer an essential gateway for the activation of caspases in the intrinsic apoptotic pathway.
    Type of Medium: Online Resource
    ISSN: 1469-221X , 1469-3178
    URL: Article
    DOI: 10.1038/sj.embor.7400375
    Language: English
    Publisher: EMBO
    Publication Date: 2005
    detail.hit.zdb_id: 2025376-X
    SSG: 12
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  • 10
    Online Resource
    Online Resource
    VDAC2 Inhibits BAK Activation and Mitochondrial Apoptosis
    American Association for the Advancement of Science (AAAS) ; 2003
    In:  Science Vol. 301, No. 5632 ( 2003-07-25), p. 513-517
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 301, No. 5632 ( 2003-07-25), p. 513-517
    Abstract: The multidomain proapoptotic molecules BAK or BAX are required to initiate the mitochondrial pathway of apoptosis. How cells maintain the potentially lethal proapoptotic effector BAK in a monomeric inactive conformation at mitochondria is unknown. In viable cells, we found BAK complexed with mitochondrial outer-membrane protein VDAC2, a VDAC isoform present in low abundance that interacts specifically with the inactive conformer of BAK. Cells deficient in VDAC2, but not cells lacking the more abundant VDAC1, exhibited enhanced BAK oligomerization and were more susceptible to apoptotic death. Conversely, overexpression of VDAC2 selectively prevented BAK activation and inhibited the mitochondrial apoptotic pathway. Death signals activate “BH3-only” molecules such as tBID, BIM, or BAD, which displace VDAC2 from BAK, enabling homo-oligomerization of BAK and apoptosis. Thus, VDAC2, an isoform restricted to mammals, regulates the activity of BAK and provides a connection between mitochondrial physiology and the core apoptotic pathway.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.1083995
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2003
    detail.hit.zdb_id: 128410-1
    detail.hit.zdb_id: 2066996-3
    detail.hit.zdb_id: 2060783-0
    SSG: 11
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