HMGB1 and HMGB2 Cell-specifically Down-regulate the p53- and p73-dependent Sequence-specific Transactivation from the Human Bax Gene Promoter

Štros, Michal; Ozaki, Toshinori; Bačı́ková, Alena; Kageyama, Hajime; Nakagawara, Akira

doi:10.1074/jbc.m110233200

Cited by 170 publications

(135 citation statements)

References 51 publications

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“…Physical and functional interactions between p53 and members of other subfamilies of HMG proteins, such as the HMGB proteins, have been previously described. 33,34 However, the different subfamilies possess divergent functions. 35 Indeed, the reported HMGB-mediated modulation of p53 transcriptional activity seems to be relevant in normal conditions while the HMGA1-mediated inhibition of p53 apoptotic function, which we are reporting here, might be mostly relevant for tumour formation.…”

Section: Discussionmentioning

confidence: 99%

High Mobility Group A1 (HMGA1) proteins interact with p53 and inhibit its apoptotic activity

et al. 2005

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HMGA gene overexpression and rearrangements are frequent in several tumours, but their oncogenic function is still unclear. Here we report of a physical and functional interaction between High Mobility Group A1 (HMGA1) protein and p53 oncosuppressor. We found that HMGA1 binds p53 in vitro and in vivo, and both proteins are present in the same complexes bound to the Bax gene promoter. HMGA1 interferes with the p53-mediated transcription of p53 effectors Bax and p21 waf1 while cooperates with p53 in the transcriptional activation of the p53 inhibitor mdm2. This transcriptional modulation is associated with a reduced p53-dependent apoptosis in cells expressing exogenous HMGA1 and p53, or in cells expressing endogenously the proteins and in which p53 was activated by UV-irradiation. Furthermore, antisense inhibition of HMGA1b expression dramatically increases the UV-induced p53-mediated apoptosis. These data define a new physical and functional interaction between HMGA1 and p53 that modulates transcription of p53 target genes and inhibits apoptosis.

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Section: Discussionmentioning

confidence: 99%

High Mobility Group A1 (HMGA1) proteins interact with p53 and inhibit its apoptotic activity

et al. 2005

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“…With rapid advances in cancer researching in the past decade, it is well accepted that HMGB1 is associated with each of the six hallmarks (Tang et al, 2010). Despite its critical roles in nucleus, such as DNA repair, interaction with transcriptional factors like p53, p73 and Rb protein, the functions of extracellular HMGB1 receive a great deal of attention recently (Stros et al, 2002;Banerjee et al, 2003;Krynetski et al, 2003;Jiao et al, 2007). It is noteworthy that HMGB1protein released from cancer cells is a double-edged sword: it promotes tumor neoangiogenesis; it triggers protective anti-neoplastic T-cell responses (Campana et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

High Mobility Group Box 1 Protein Is Methylated and Transported to Cytoplasm in Clear Cell Renal Cell Carcinoma

Zhao²,

Ding³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Background:The high mobility group box 1 (HMGB1) protein is a widespread nuclear protein present in most cell types. It typically locates in the nucleus and functions as a nuclear cofactor in transcription regulation. However, HMGB1 can also localize in the cytoplasm and be released into extracellular matrix, where it plays critical roles in carcinogenesis and inflammation. However, it remains elusive whether HMGB1 is relocated to cytoplasm in clear cell renal cell carcinoma (ccRCC). Methods: Nuclear and cytoplasmic proteins were extracted by different protocols from 20 ccRCC samples and corresponding adjacent renal tissues. Western blotting and immunohistochemistry were used to identify the expression of HMGB1 in ccRCC. To elucidate the potential mechanism of HMGB1 cytoplasmic translocation, HMGB1 proteins were enriched by immunoprecipitation and analyzed by mass spectrometry (MS). Results: The HMGB1 protein was overexpressed and partially localized in cytoplasm in ccRCC samples (12/20, 60%, p<0.05). Immunohistochemistry results indicated that ccRCC of high nuclear grade possess more HMGB1 relocation than those with low grade (p<0.05). Methylation of HMGB1 at lysine 112 in ccRCC was detected by MS. Bioinformatics analysis showed that post-translational modification might affect the binding ability to DNA and mediate its translocation. Conclusion: Relocation of HMGB1 to cytoplasm was confirmed in ccRCC. Methylation of HMGB1 at lysine 112 might the redistribution of this cofactor protein.

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“…Notch1 is expressed in developing articular cartilage surface (45) in a pattern similar to HMGB2 (17), indicating that Notch might be involved in Lef1-HMGB2 complex formation in temporally and spatially specific patterns during cartilage formation. HMGB2 has been reported to interact with steroid receptors (46), p53 and p73 (47). Stros et al reported that B-box within human HMGB1 required the TKKKFKD motif that is included in the linker for interaction with p73, whereas A-box itself can bind p73 (47).…”

Section: Discussionmentioning

confidence: 99%

“…HMGB2 has been reported to interact with steroid receptors (46), p53 and p73 (47). Stros et al reported that B-box within human HMGB1 required the TKKKFKD motif that is included in the linker for interaction with p73, whereas A-box itself can bind p73 (47). It has also been shown that A-box, which contains the linker region within HMGB1, can interact with p53 (48).…”

Section: Discussionmentioning

confidence: 99%

Chromatin protein HMGB2 regulates articular cartilage surface maintenance via β-catenin pathway

Taniguchi

Caramés

Kawakami

et al. 2009

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

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The superficial zone (SZ) of articular cartilage is critical in maintaining tissue function and homeostasis and represents the site of the earliest changes in osteoarthritis. Mechanisms that regulate the unique phenotype of SZ chondrocytes and maintain SZ integrity are unknown. We recently demonstrated that expression of the chromatin protein high mobility group box (HMGB) protein 2 is restricted to the SZ in articular cartilage suggesting a transcriptional regulation involving HMGB2 in SZ. Here, we show that an interaction between HMGB2 and the Wnt/␤-catenin pathway regulates the maintenance of the SZ. We found that the Wnt/␤-catenin pathway is active specifically in the SZ in normal mouse knee joints and colocalizes with HMGB2. Both Wnt signaling and HMGB2 expression decrease with aging in mouse joints. Our molecular studies show that HMGB2 enhances the binding of Lef-1 to its target sequence and potentiates transcriptional activation of the Lef-1-␤-catenin complex. The HMG domain within HMGB2 is crucial for interaction with Lef-1, suggesting that both HMGB2 and HMGB1 may be involved in this function. Furthermore, conditional deletion of ␤-catenin in cultured mouse chondrocytes induced apoptosis. These findings define a pathway where protein interactions of HMGB2 and Lef-1 enhance Wnt signaling and promote SZ chondrocyte survival. Loss of the HMGB2-Wnt signaling interaction is a new mechanism in aging-related cartilage pathology.aging ͉ osteoarthritis ͉ apoptosis ͉ superficial zone A rticular cartilage is a tissue that provides biomechanical properties that allow near frictionless joint movement and dispersion of mechanical loads. Cartilage is composed of a single cell lineage but differences in the organization, phenotype and function of cells in the various layers of cartilage have been recognized (1-4). The superficial zone (SZ) is the most unique. SZ cells produce lubricin, also termed proteoglycan-4 (PRG4) or superficial zone protein (SZP), an important joint lubricant (5-7), and are more responsive to stimulation by catabolic cytokines such as IL-1 (8). Recent studies also suggest that the SZ contains cells that express mesenchymal stem cell markers (9-11).Articular cartilage is among the tissues that undergo profound aging-related changes and aging represents the major risk factor for osteoarthritis (OA), the most prevalent joint disease (12). Agingrelated changes in cartilage include reduced cellularity, increased apoptosis and altered cellular responses to growth factors, cytokines and mechanical stress (13-15). Cartilage changes in aging and OA begin in the SZ and once the SZ is disrupted this is followed by progressive erosion of the remaining cartilage layers (16).To address mechanisms that maintain the unique phenotype of SZ cells we performed gene expression analyses and observed that expression of the chromatin protein HMGB2 is restricted to the SZ (17). Joint aging in humans and mice leads to loss of HMGB2 expression and this is correlated with the onset of OA-like changes. Mice deficient in Hm...

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HMGB1 and HMGB2 Cell-specifically Down-regulate the p53- and p73-dependent Sequence-specific Transactivation from the Human Bax Gene Promoter

Cited by 170 publications

References 51 publications

High Mobility Group A1 (HMGA1) proteins interact with p53 and inhibit its apoptotic activity

High Mobility Group A1 (HMGA1) proteins interact with p53 and inhibit its apoptotic activity

High Mobility Group Box 1 Protein Is Methylated and Transported to Cytoplasm in Clear Cell Renal Cell Carcinoma

Chromatin protein HMGB2 regulates articular cartilage surface maintenance via β-catenin pathway

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