Size matters: of the small HSP27 and its large oligomers

Garrido, Carmen

doi:10.1038/sj.cdd.4401005

Cited by 102 publications

(79 citation statements)

References 15 publications

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“…These observations raise some interesting questions about the function of the phosphorylated and unphosphorylated forms of Hsp-27 following Dox treatment of MCF7 cells because of the distinct mechanisms of action (Bruey et al 2000;Garrido 2002;Parcellier et al 2003Parcellier et al , 2005. In our study, phosphorylated Hsp-27 did not appear to be directly involved in migration following Dox treatment because pHsp-27 was localised to the nuclei of migrating cells, whereas total Hsp-27 was markedly increased in processes of migratory cells that were involved in cell-cell contact.…”

Section: Discussionmentioning

confidence: 51%

“…Thus, unphosphorylated Hsp-27 exist as large oligomeric complexes (200-800 kDa) that are required for specific functions such as its action as a molecular chaperone (Garrido 2002;Rogalla et al 1999). However, phosphorylation at specific serine residues (ser-15, 78 and 82) causes these large complexes to dissociate and form smaller oligomers (tetramer, dimer or monomer), which act in a different manner to larger unphosphorylated complexes.…”

Section: Discussionmentioning

confidence: 99%

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Hsp-27 induction requires POU4F2/Brn-3b TF in doxorubicin-treated breast cancer cells, whereas phosphorylation alters its cellular localisation following drug treatment

Fujita

Ounzain

Wang

et al. 2011

Cell Stress and Chaperones

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POU4F2/Brn-3b transcription factor (referred to as Brn-3b) is elevated in >60% of breast cancers and profoundly alters growth and behaviour of cancer cells by regulating distinct subsets of target genes. Previous studies showed that Brn-3b was required to maximally transactivate small heat shock protein, HSPB1/Hsp-27 (referred to as , and consequently, Brn-3b expression correlated well with Hsp27 levels in human breast biopsies. In these studies, we showed that Brn-3b is increased in MCF7 breast cancer cells that survive following treatment with chemotherapeutic drug doxorubicin (Dox) with concomitant increases in Hsp-27 expression. Targeting of Brn3b using short interfering RNA reduced Hsp-27 in Doxtreated cells, suggesting that Brn-3b regulates Hsp-27 expression under these conditions. Wound healing assays showed increased Brn-3b in Dox-treated migratory cells that also express Hsp-27. Interestingly, Hsp-27 phosphorylation and cellular localisation are also significantly altered at different times following Dox treatment. Thus, phosphoHsp-27 (p-Hsp27) protein displayed widespread distribution after 24 hrs of Dox treatment but was restricted to the nucleus after 5 days. However, in drug-resistant cells (grown in Dox for >1 month), p-Hsp-27 was excluded from nuclei and most of the cytoplasm and appeared to be associated with the cell membrane. Studies to determine how this protein promotes survival and migration in breast cancer cells showed that the protective effects were conferred by unphosphorylated Hsp-27 protein.

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Section: Discussionmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Hsp-27 induction requires POU4F2/Brn-3b TF in doxorubicin-treated breast cancer cells, whereas phosphorylation alters its cellular localisation following drug treatment

Fujita

Ounzain

Wang

et al. 2011

Cell Stress and Chaperones

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“…This indicates that the insolubilization observed in the above experiments is probably not the formation of productive stress granules (30) but rather represents non-productive and proapoptotic complex formation with irreversibly denatured proteins (4) resulting in irreversible damage of the stressed cells and/or a withdraw of Hsp25 from its anti-apoptotic functions (50), such as cytochrome c (51) or Daxx binding (52). Interestingly, the p38 MAPK cascade also exhibits a pro-apoptotic function (53), and p38-deficient fibroblasts are more resistant against stress stimuli, such as UV or serum deprivation (43).…”

Section: Discussionmentioning

confidence: 99%

Analysis of Properties of Small Heat Shock Protein Hsp25 in MAPK-activated Protein Kinase 2 (MK2)-deficient Cells

Vertii

Hakim

Kotlyarov

et al. 2006

Journal of Biological Chemistry

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Small heat shock proteins (sHsps) exist in dynamic oligomeric complexes and display diverse biological functions ranging from chaperone properties to modulator of apoptosis. So far, the role of stress-dependent phosphorylation of mammalian sHsps for its structure and function has been analyzed by using various phosphorylation site mutants overexpressed in different cell types as well as by non-exclusive inhibitors of the p38 MAPK cascade. Here we investigate the role of phosphorylation of endogenous sHsp in a genetic model lacking the major Hsp25 kinase, the MAP kinase-activated protein kinase MK2. We demonstrate that in MK2-deficient fibroblasts, where no stress-dependent phosphorylation of Hsp25 at Ser 86 and no in vitro binding to 14-3-3 was detectable, stress-dependent disaggregation of endogenous Hsp25 complexes is impared and kinetics of arsenite-dependent, H 2 O 2 -dependent, and sublethal heat shock-induced insolubilization of Hsp25 is delayed. Similarly, green fluorescent protein-tagged Hsp25 shows retarded subcellular accumulation into stress granules in MK2-deficient cells after arsenite treatment. Decreased insolubilization of Hsp25 in MK2-deficient cells correlates with increased resistance against arsenite, H 2 O 2 , and sublethal heat shock treatment and with decreased apoptosis. In contrast, after severe, lethal heat shock MK2-deficient embryonic fibroblasts cells show fast and complete insolubilization of Hsp25 independent of MK2 and no increased stress resistance. Hence, MK2-dependent formation of insoluble stress granules and irreversible cell damage by oxidative stresses and sublethal heat shock correlate and only upon severe, lethal heat shock MK2-independent processes could determine insolubilization of Hsp25 and are more relevant for cellular stress damage.

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“…Hsp27 exhibits remarkable versatility in its ability to form oligomers of varying size, to bind a wide range of unfolding substrates, and to recognize specific, folded proteins, 7,8 yet detailed, structure-based mechanisms for these functional properties and their relationships to each other have not been developed. This study is an effort toward that goal that is based on correlating the oligomeric state of the protein with its chaperone activity and subunit-exchange kinetics to define the functional contributions of the N-and C-sequences of the protein.…”

Section: Discussionmentioning

confidence: 99%

“…For example, Hsp27 exhibits chaperone activity, 2 inhibits cytochrome c-induced apoptosis by inhibiting activation of procaspase-9, 3 modulates oxidative stress and regulates the cytoskeleton. [4][5][6][7][8] In addition, overexpression of Hsp27 by tumor cells increases their tumorigenicity and protects against cell death triggered by a number of stimuli, e.g., hyperthermia, oxidative stress, staurosporine, ligation of the Fas/ApoÀ1/CD95 death receptor, and cytotoxic drugs. 9 Mutant forms of Hsp27 have been linked to human neuromuscular disorders such as axonal CharcotÀMarieÀTooth disease 10,11 and distal hereditary motor neuropathy, 12 and Hsp27 accumulates in individuals with various neurodegenerative disorders, including Alzheimer's, Parkinson's, Alexander's, and CreutzfeldtÀJakob diseases and multiple sclerosis.…”

Section: Hsp27 (Or Hspb1mentioning

confidence: 99%

Roles of the N‐ and C‐terminal sequences in Hsp27 self‐association and chaperone activity

Lelj-Garolla

Mauk

2011

Protein Science

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The small heat shock protein 27 (Hsp27 or HSPB1) is an oligomeric molecular chaperone in vitro that is associated with several neuromuscular, neurological, and neoplastic diseases. Although aspects of Hsp27 biology are increasingly well known, understanding of the structural basis for these involvements or of the functional properties of the protein remains limited. As all 11 human small heat shock proteins (sHsps) possess an a-crystallin domain, their varied functional and physiological characteristics must arise from contributions of their nonconserved sequences. To evaluate the role of two such sequences in Hsp27, we have studied three Hsp27 truncation variants to assess the functional contributions of the nonconserved N-and C-terminal sequences. The N-terminal variants D1-14 and D1-24 exhibit little chaperone activity, somewhat slower but temperature-dependent subunit exchange kinetics, and temperature-independent self-association with formation of smaller oligomers than wild-type Hsp27. The C-terminal truncation variants exhibit chaperone activity at 40°C but none at 20°C, limited subunit exchange, and temperatureindependent self-association with an oligomer distribution at 40°C that is very similar to that of wild-type Hsp27. We conclude that more of the N-terminal sequence than simply the WPDF domain is essential in the formation of larger, native-like oligomers after binding of substrate and/or in binding of Hsp27 to unfolding peptides. On the other hand, the intrinsically flexible C-terminal region drives subunit exchange and thermally-induced unfolding, both of which are essential to chaperone activity at low temperature and are linked to the temperature dependence of Hsp27 self-association.

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Size matters: of the small HSP27 and its large oligomers

Cited by 102 publications

References 15 publications

Hsp-27 induction requires POU4F2/Brn-3b TF in doxorubicin-treated breast cancer cells, whereas phosphorylation alters its cellular localisation following drug treatment

Hsp-27 induction requires POU4F2/Brn-3b TF in doxorubicin-treated breast cancer cells, whereas phosphorylation alters its cellular localisation following drug treatment

Analysis of Properties of Small Heat Shock Protein Hsp25 in MAPK-activated Protein Kinase 2 (MK2)-deficient Cells

Roles of the N‐ and C‐terminal sequences in Hsp27 self‐association and chaperone activity

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