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  1. Article ; Online: The role of ubiquitination in the direct mitochondrial death program of p53.

    Marchenko, Natasha D / Moll, Ute M

    Cell cycle (Georgetown, Tex.)

    2007  Volume 6, Issue 14, Page(s) 1718–1723

    Abstract: p53 ubiquitination at C-terminal lysines by MDM2 and other E3 ligases had been considered a straightforward negative regulation of p53 with only one function, that is marking the protein for proteasomal degradation. In this review, we will focus on the ... ...

    Abstract p53 ubiquitination at C-terminal lysines by MDM2 and other E3 ligases had been considered a straightforward negative regulation of p53 with only one function, that is marking the protein for proteasomal degradation. In this review, we will focus on the recently uncovered activating role of ubiquitination in the transcription-independent direct mitochondrial death program of p53.
    MeSH term(s) Animals ; Apoptosis/physiology ; Mitochondria/metabolism ; Protein Transport/physiology ; Proto-Oncogene Proteins c-mdm2/metabolism ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism ; Ubiquitin/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination
    Chemical Substances Tumor Suppressor Protein p53 ; Ubiquitin ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27)
    Language English
    Publishing date 2007-05-25
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2146183-1
    ISSN 1551-4005 ; 1538-4101 ; 1554-8627
    ISSN (online) 1551-4005
    ISSN 1538-4101 ; 1554-8627
    DOI 10.4161/cc.6.14.4503
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Monoubiquitylation promotes mitochondrial p53 translocation.

    Marchenko, Natasha D / Wolff, Sonja / Erster, Susan / Becker, Kerstin / Moll, Ute M

    The EMBO journal

    2007  Volume 26, Issue 4, Page(s) 923–934

    Abstract: A major function of the p53 tumor suppressor is the induction of a pleiotropic apoptotic program in response to stress through transcription-dependent and -independent mechanisms. In particular, this includes a direct apoptotic role of p53 at the ... ...

    Abstract A major function of the p53 tumor suppressor is the induction of a pleiotropic apoptotic program in response to stress through transcription-dependent and -independent mechanisms. In particular, this includes a direct apoptotic role of p53 at the mitochondria. Stress-induced p53 translocation to the mitochondria with subsequent outer membrane permeabilization is a common early component in p53-mediated apoptosis in normal and transformed cells. However, the mechanism of p53 delivery to the mitochondria remains unknown. Here, we show that the cytoplasm contains a separate and distinct p53 pool that is the major source for p53 translocation to the mitochondria upon its stress-induced stabilization. Using various manipulations that enhance or diminish p53 ubiquitylation, our data provide evidence that Mdm2-mediated monoubiquitylation of p53 greatly promotes its mitochondrial translocation and thus its direct mitochondrial apoptosis. On the other hand, p53 does not require Mdm2 as a shuttler. Upon arrival at the mitochondria, our data suggest that p53 undergoes rapid deubiquitylation by mitochondrial HAUSP via a stress-induced mitochondrial p53-HAUSP complex. This generates the apoptotically active non-ubiquitylated p53. Taken together, we propose a novel model for mitochondrial p53 targeting, whereby a distinct cytoplasmic pool of stabilized monoubiquitylated p53, generated in resting cells by basal levels of Mdm2-type ligases, is subject to a binary switch from a fate of inactivation via subsequent polyubiquitylation and degradation in unstressed cells, to a fate of activation via mitochondrial trafficking.
    MeSH term(s) Apoptosis/physiology ; Camptothecin ; Cell Line, Tumor ; Cytoplasm/metabolism ; Endopeptidases/metabolism ; Humans ; Immunoblotting ; Immunoprecipitation ; Mitochondria/metabolism ; Mitochondria/physiology ; Models, Biological ; Protein Transport/physiology ; Proto-Oncogene Proteins c-mdm2/metabolism ; Tumor Suppressor Protein p53/metabolism ; Ubiquitin/metabolism ; Ubiquitin Thiolesterase ; Ubiquitin-Specific Peptidase 7
    Chemical Substances Tumor Suppressor Protein p53 ; Ubiquitin ; MDM2 protein, human (EC 2.3.2.27) ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27) ; Endopeptidases (EC 3.4.-) ; USP7 protein, human (EC 3.4.19.12) ; Ubiquitin Thiolesterase (EC 3.4.19.12) ; Ubiquitin-Specific Peptidase 7 (EC 3.4.19.12) ; Camptothecin (XT3Z54Z28A)
    Language English
    Publishing date 2007-02-21
    Publishing country England
    Document type Comparative Study ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 586044-1
    ISSN 1460-2075 ; 0261-4189
    ISSN (online) 1460-2075
    ISSN 0261-4189
    DOI 10.1038/sj.emboj.7601560
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: WT p53, but Not Tumor-derived Mutants, Bind to Bcl2 via the DNA Binding Domain and Induce Mitochondrial Permeabilization

    Tomita, York / Marchenko, Natasha / Erster, Susan / Nemajerova, Alice / Dehner, Alexander / Klein, Christian / Pan, Hongguang / Kessler, Horst / Pancoska, Petr / Moll, Ute M

    Journal of biological chemistry. 2006 Mar. 31, v. 281, no. 13

    2006  

    Abstract: ... determined by surface plasmon resonance analysis (BIAcore) to have a dominant component K[subscript D] 535 ...

    Abstract The induction of apoptosis by p53 in response to cellular stress is its most conserved function and crucial for p53 tumor suppression. We recently reported that p53 directly induces oligomerization of the BH1,2,3 effector protein Bak, leading to outer mitochondrial membrane permeabilization (OMMP) with release of apoptotic activator proteins. One important mechanism by which p53 achieves OMMP is by forming an inhibitory complex with the anti-apoptotic BclXL protein. In contrast, the p53 complex with the Bcl2 homolog has not been interrogated. Here we have undertaken a detailed characterization of the p53-Bcl2 interaction using structural, biophysical, and mutational analyses. We have identified the p53 DNA binding domain as the binding interface for Bcl2 using solution NMR. The affinity of the p53-Bcl2 complex was determined by surface plasmon resonance analysis (BIAcore) to have a dominant component K[subscript D] 535 ± 24 nM. Moreover, in contrast to wild type p53, endogenous missense mutants of p53 are unable to form complexes with endogenous Bcl2 in human cancer cells. Functionally, these mutants are all completely or strongly compromised in mediating OMMP, as measured by cytochrome c release from isolated mitochondria. These data implicate p53-Bcl2 complexes in contributing to the direct mitochondrial p53 pathway of apoptosis and further support the notion that the DNA binding domain of p53 is a dual function domain, mediating both its transactivation function and its direct mitochondrial apoptotic function.
    Language English
    Dates of publication 2006-0331
    Size p. 8600-8606.
    Publishing place American Society for Biochemistry and Molecular Biology
    Document type Article
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    Database NAL-Catalogue (AGRICOLA)

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