Localization of HMG chromosomal proteins in the nucleus and cytoplasm by microinjection of functional antibody fragments into living fibroblasts

Einck, Leo; Soares, Nirmolini; Bustin, Michael

doi:10.1016/0014-4827(84)90631-1

Cited by 16 publications

(8 citation statements)

References 41 publications

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“…15,16 Electrophoretic analysis of nuclear and cytoplasmic fibroblasts fractions indicated that HMGB1 is present in both cell cytoplasm and nucleus with a predominance of the cytoplasmic fraction. 17 Considered a prototype “alarmin” with critical roles in pathogenicity of many conditions, HMGB1 can play key physiologic roles when passively released in the extracellular space by dying cells. 18 Extracellular HMGB1 has cell growth, pro-angiogenic, mitotic activity and antibacterial roles.…”

Section: Discussionmentioning

confidence: 99%

High Mobility Group-Box 1 (HMGB1) levels are increased in amniotic fluid of women with intra-amniotic inflammation-determined preterm birth, and the source may be the damaged fetal membranes

et al. 2016

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Background High Mobility Group Box-1 (HMGB1) is considered a prototype alarmin molecule. Upon its extracellular release, HMGB1 engages pattern recognition receptors and the Receptor for Advanced Glycation End (RAGE) followed by an outpouring of inflammatory cytokines, including interleukin (IL)-6. Methods We assayed the amniotic fluid (AF) levels of HMGB1 and IL-6 in 255 women that either had a normal pregnancy outcome or delivered preterm. Immunohistochemistry on fetal membranes was used for cellular localization and validation of immunoassay findings. HMGB1 also was analyzed in amniochorion tissue explants subjected to endotoxin. Results AF HMGB1 levels are not gestational age regulated but increased in women with intra-amniotic inflammation and preterm birth. The likely source is the damaged amniochorion, as demonstrated by immunohistochemistry and explant experiments. Conclusions Our research supports a role for HMGB1 in the inflammatory response leading to preterm birth. As a delayed phase cytokine, in utero exposure to elevated HMGB1 levels may have an impact on the newborn beyond the time of birth.

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Section: Discussionmentioning

confidence: 99%

High Mobility Group-Box 1 (HMGB1) levels are increased in amniotic fluid of women with intra-amniotic inflammation-determined preterm birth, and the source may be the damaged fetal membranes

et al. 2016

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“…Subsequent studies investigated the levels and distribution of HMGB1 between the nucleus and cytoplasm in different cells and tissues. Localization of HMGB1 in the cytoplasm has been confirmed in living fibroblasts (Einck et al, 1984), thymocytes (Guillet et al, 1990) and several different tissues (e.g., liver, kidney, heart, and lung) (Kuehl et al, 1984). The normal ratio of nuclear to cytoplasmic HMGB1 is about 30:1 (Kuehl et al, 1984).…”

Section: Hmgb1 Functionmentioning

confidence: 91%

HMGB1 in health and disease

Kang

Chen

Zhang

et al. 2014

Molecular Aspects of Medicine

803

828

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Complex genetic and physiological variations as well as environmental factors that drive emergence of chromosomal instability, development of unscheduled cell death, skewed differentiation, and altered metabolism are central to the pathogenesis of human diseases and disorders. Understanding the molecular bases for these processes is important for the development of new diagnostic biomarkers, and for identifying new therapeutic targets. In 1973, a group of non-histone nuclear proteins with high electrophoretic mobility was discovered and termed High-Mobility Group (HMG) proteins. The HMG proteins include three superfamilies termed HMGB, HMGN, and HMGA. High-mobility group box 1 (HMGB1), the most abundant and well-studied HMG protein, senses and coordinates the cellular stress response and plays a critical role not only inside of the cell as a DNA chaperone, chromosome guardian, autophagy sustainer, and protector from apoptotic cell death, but also outside the cell as the prototypic damage associated molecular pattern molecule (DAMP). This DAMP, in conjunction with other factors, thus has cytokine, chemokine, and growth factor activity, orchestrating the inflammatory and immune response. All of these characteristics make HMGB1 a critical molecular target in multiple human diseases including infectious diseases, ischemia, immune disorders, neurodegenerative diseases, metabolic disorders, and cancer. Indeed, a number of emergent strategies have been used to inhibit HMGB1 expression, release, and activity in vitro and in vivo. These include antibodies, peptide inhbitiors, RNAi, anti-coagulants, endogenous hormones, various chemical compounds, HMGB1-receptor and signaling pathway inhibition, artificial DNAs, physical strategies including vagus nerve stimulation and other surgical approaches. Future work further investigating the details of HMGB1 localizationtion, structure, post-translational modification, and identifccation of additional partners will undoubtedly uncover additional secrets regarding HMGB1’s multiple functions.

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“…It has been argued that some of the nuclear proteins (see Introduction) that have been shown to preferentially bind to cis-DDP-modified DNA might act to block repair of the damaged DNA. This might explain the specific lethality of the (37,38), and a role for this protein in the biological activity of cis-Pt has been suggested by several groups. Although these experiments do not distinguish possible differences in H1 affinity between particular types of cis-Pt adducts, they clearly establish the point that H1 is very strongly bound to some of these.…”

Section: Resultsmentioning

confidence: 99%

The major chromatin protein histone H1 binds preferentially to cis -platinum-damaged DNA

Yaneva

Leuba

Holde

et al. 1997

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

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Both cis-diamminedichloroplatinum(II) (cisplatin or cis-DDP) and trans-diamminedichloroplatinum (II) form covalent adducts with DNA. However, only the cis isomer is a potent anticancer agent. It has been postulated that the selective action of cis-DDP occurs through specific binding of nuclear proteins to cis-DDP-damaged DNA sites and that binding blocks DNA repair. We find that a very abundant nuclear protein, the linker histone H1, binds much more strongly to cis-platinated DNA than to trans-platinated or unmodified DNA. In competition experiments, H1 is shown to bind much more strongly than HMG1, which had been previously considered a major candidate for such binding in vivo.cis-Diamminedichloroplatinum(II) (cisplatin or cis-DDP) is a potent chemotherapeutic agent widely used in the clinical practice to treat several types of human malignancies. The therapeutic effect is believed to arise as a consequence of cis-DDP binding to DNA (1), but it cannot be solely explained on the basis of DNA binding because a number of closely related compounds, among which is included the geometric isomer trans-DDP, are not effective agents although they also damage DNA. The differential biological effect of different Pt compounds may lie in the differential processing of different Pt-DNA adducts by the cell. The realization that different adducts may be processed differently suggested that certain proteins might enhance or block DNA repair by specifically interacting with cis-DDP-modified DNA; this has focused research toward identifying such proteins.cis-DDP causes the formation of two major intrastrand DNA adducts, 1,2-d(GpG) and d(ApG) cross-links in which the two chloride ions of cis-DDP are replaced by the N7 atoms of guanine and adenine. An intrastrand cross-link may also be formed, at a much lower frequency, at d(GpXpG), where X is any base. Other minor adducts may also arise, including interstrand cross-links involving guanine residues on opposite strands. Biochemical and structural analyses of both intra-and interstrand cis-DDP adducts (2, 3) reveal major distortions of the DNA double helix, including bending and unwinding (for review, see ref. 4). The therapeutically inactive trans-DDP is incapable of forming the 1,2-(GpG) and d(ApG) adducts for stereochemical reasons. It does form 1,3-intrastrand links and also cross-links opposite strands, but although cis-DDP reacts with guanine residues in d(GpC), the trans-isomer preferentially cross-links complementary guanine and cytosine residues (5). The different kinds of cross-links created by the cis-and trans-DDP are illustrated schematically for one specific DNA fragment used in this work (see Fig. 2 A).Recent years have witnessed the discovery of a number of cellular proteins, mostly with still unidentified in vivo functions, that recognize and bind selectively to cis-DDP-modified DNA. These include the relatively abundant chromatin nonhistone proteins HMG1 and HMG2 (6, 7), the human structure-specific recognition protein 1 SSRP1 (8, 9), the yeast intrastrand c...

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Localization of HMG chromosomal proteins in the nucleus and cytoplasm by microinjection of functional antibody fragments into living fibroblasts

Cited by 16 publications

References 41 publications

High Mobility Group-Box 1 (HMGB1) levels are increased in amniotic fluid of women with intra-amniotic inflammation-determined preterm birth, and the source may be the damaged fetal membranes

High Mobility Group-Box 1 (HMGB1) levels are increased in amniotic fluid of women with intra-amniotic inflammation-determined preterm birth, and the source may be the damaged fetal membranes

HMGB1 in health and disease

The major chromatin protein histone H1 binds preferentially to cis -platinum-damaged DNA

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