HSF2 protects against proteotoxicity by maintaining cell-cell adhesion

ABSTRACTCellular ability to maintain proper protein homeostasis (proteostasis) is essential for survival upon protein-damaging conditions. Heat shock transcription factor 2 (HSF2) is one of the human HSFs activated in response to proteotoxic stress. HSF2 is dispensable for cell survival during acute heat stress, but its amount and DNA-binding activity increase under prolonged proteotoxic stress conditions, such as proteasome inhibition. Nevertheless, the specific role(s) of HSF2 and the global HSF2-dependent gene expression profile during sustained stress have remained elusive. We found that HSF2 is required for cell survival during prolonged proteotoxicity, as shown by treating wild-type and HSF2-deficient human osteosarcoma U2OS cells with the proteasome inhibitor Bortezomib. Strikingly, our RNA-seq analyses revealed that HSF2 disruption leads to marked downregulation of cadherin superfamily genes and subsequent functional impairment of cadherin-mediated cell-cell adhesion. We propose HSF2 as a key regulator of genes belonging to the cadherin superfamily. We also demonstrate that HSF2-dependent downregulation of cadherin-mediated cell-cell adhesion predisposes U2OS cells to Bortezomib-induced proteotoxic stress. In conclusion, we show that by maintaining cell-cell adhesion HSF2 is essential for cell survival and thereby we describe a novel regime in the HSF-mediated protection against stress-induced protein damage.

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Lymphoid adhesion promotes human thymic epithelial cell survival via NF-(kappa)B activation

Journal of Cell Science ◽

10.1242/jcs.113.1.169 ◽

2000 ◽

Vol 113 (1) ◽

pp. 169-177

Author(s):

M.T. Scupoli ◽

E. Fiorini ◽

P.C. Marchisio ◽

O. Poffe ◽

E. Tagliabue ◽

...

Keyword(s):

Cell Adhesion ◽

Epithelial Cell ◽

Epithelial Cells ◽

Cell Survival ◽

Functional Differentiation ◽

Binding Activity ◽

Thymic Epithelial Cells ◽

Thymic Epithelial Cell ◽

Nf Kappa B ◽

Promoting Effect

Inside the thymus, thymic epithelial cells and thymocytes show an interdependent relationship for their functional differentiation and development. As regards possible interdependency for their mutual survival, it is clear that lympho-epithelial adhesion can control the survival of developing thymocytes whereas the effects of lymphoid adhesion on epithelial cell survival have never been described. To address this issue, we performed co-cultures between normal human thymic epithelial cells (TEC) and a mature lymphoid T cell line (H9) or unfractionated thymocytes. TEC were induced to apoptosis by growth factor deprivation and the level of cell death was measured by flow cytometry. TEC stimulated by cell adhesion showed a significant reduced apoptosis when compared to the control and this phenomenon was associated with increased binding activity of NF-(kappa)B, as measured by gel shift analysis. The activation of NF-(kappa)B was necessary to promote survival, since its inhibition by acetyl salicylic acid prevented the promoting effect. The mAb-mediated crosslinking of (alpha)(3)(beta)(1) was considered as a potential inducer of TEC survival, since we have previously demonstrated that the engagement of this integrin was able to induce NF-(kappa)B activation in TEC. The crosslinking of (alpha)(3)(beta)(1), which clustered at the lympho-epithelial contact sites, partially reproduced the promoting activity of cell adhesion. These results highlight that lympho-epithelial adhesion can control the survival of thymic epithelial cells through an intracellular pathway which requires the activation of NF-(kappa)B and is triggered by integrins of the (beta)(1) family.

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Activation of Phosphatidylinositol 3-Kinase/Protein Kinase B by Corticotropin-Releasing Factor in Human Monocytes

Endocrinology ◽

10.1210/en.2008-1810 ◽

2009 ◽

Vol 150 (10) ◽

pp. 4606-4614 ◽

Cited By ~ 10

Author(s):

Christina Chandras ◽

Yassemi Koutmani ◽

Efi Kokkotou ◽

Charalabos Pothoulakis ◽

Katia P. Karalis

Keyword(s):

Cell Survival ◽

Inflammatory Diseases ◽

Nuclear Factor Κb ◽

Binding Activity ◽

Corticotropin Releasing Factor ◽

Human Monocytes ◽

Phosphatidylinositol 3 Kinase ◽

Peripheral Tissues ◽

Dna Binding Activity ◽

Phosphatidylinositol 3

Abstract Corticotropin-releasing factor (CRF) exerts proinflammatory effects in peripheral tissues, whereas the intracellular pathways mediating these effects have not been completely characterized yet. We have previously shown that CRF induces nuclear factor-κB DNA-binding activity in mouse and human leukocytes. Here we demonstrate that in the human monocytic THP-1 cells, CRF activates the phosphatidylinositol 3-kinase (PI3K)/Akt and ERK1/2 pathways. These effects of CRF are mediated by corticotropin-releasing factor receptor 2 (CRF2), as suggested by their abolishment after treatment with the specific CRF2 antagonist, astressin 2B. The CRF-mediated PI3K/Akt activation induces cell survival as suggested by the stimulation of the antiapoptotic factor Bcl-2. ERK1/2 activation results in up-regulation of IL-8 expression, an effect inhibited by the CRF-induced activation of PI3K/Akt. These studies demonstrate novel effects of CRF in human monocytes mediated by the activation of PI3K/Akt. Moreover, they reveal pathway-specific effects of the CRF/CRF2 system in chemokine activation and cell survival that may be of importance for the development of novel therapeutics for inflammatory diseases.

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Multiple Cadherin Superfamily Members with Unique Expression Profiles Are Produced in Rat Testis1

Endocrinology ◽

10.1210/endo.141.2.7334 ◽

2000 ◽

Vol 141 (2) ◽

pp. 675-683 ◽

Cited By ~ 34

Author(s):

Kamin J. Johnson ◽

Sutchin R. Patel ◽

Kim Boekelheide

Keyword(s):

Cell Adhesion ◽

Messenger Rna ◽

Time Course ◽

Expression Profiles ◽

Expression Patterns ◽

Developmental Time ◽

Pcr Cloning ◽

Critical Function ◽

Cadherin Superfamily ◽

Cell Cell

Abstract Adhesion between germ and Sertoli cells is thought to be crucial for spermatogenesis. Cadherin superfamily proteins, including classic cadherins and protocadherins, are important mediators of cell-cell adhesion. Using a degenerate PCR cloning strategy, we surveyed the expression of cadherin superfamily members in rat testis. Similar to brain, testis expressed a large number of cadherin superfamily members: 7 classic cadherins of both types I and II, 14 protocadherins, 2 protocadherin-related cadherins, and 1 cadherin-related receptor-like protein. All three protocadherin families (α, β, and γ) were found in testis. Using a semiquantitative RT-PCR assay, messenger RNA expression was determined for each cadherin superfamily member during a postnatal developmental time-course and following ablation of specific testis cell types by ethanedimethanesulfonate, methoxyacetic acid, and 2,5-hexanedione. Diverse expression patterns were observed among the cadherins, suggesting that cadherin expression is cell type-specific in testis. The large number and variety of cadherin superfamily members found in testis supports a critical function for cadherin-mediated cell-cell adhesion in spermatogenesis.

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Transcription Factor SCL Is Required for c-kit Expression and c-Kit Function in Hemopoietic Cells

Journal of Experimental Medicine ◽

10.1084/jem.188.3.439 ◽

1998 ◽

Vol 188 (3) ◽

pp. 439-450 ◽

Cited By ~ 55

Author(s):

Gorazd Krosl ◽

Gang He ◽

Martin Lefrancois ◽

Frédéric Charron ◽

Paul-Henri Roméo ◽

...

Keyword(s):

Transcription Factor ◽

Cell Survival ◽

Cell Line ◽

Ectopic Expression ◽

Binding Activity ◽

Dominant Negative ◽

Hemopoietic Cells ◽

Downstream Target ◽

Helix Loop Helix ◽

Dna Binding Activity

In normal hemopoietic cells that are dependent on specific growth factors for cell survival, the expression of the basic helix-loop-helix transcription factor SCL/Tal1 correlates with that of c-Kit, the receptor for Steel factor (SF) or stem cell factor. To address the possibility that SCL may function upstream of c-kit, we sought to modulate endogenous SCL function in the CD34+ hemopoietic cell line TF-1, which requires SF, granulocyte/macrophage colony–stimulating factor, or interleukin 3 for survival. Ectopic expression of an antisense SCL cDNA (as-SCL) or a dominant negative SCL (dn-SCL) in these cells impaired SCL DNA binding activity, and prevented the suppression of apoptosis by SF only, indicating that SCL is required for c-Kit–dependent cell survival. Consistent with the lack of response to SF, the level of c-kit mRNA and c-Kit protein was significantly and specifically reduced in as-SCL– or dn-SCL– expressing cells. c-kit mRNA, c-kit promoter activity, and the response to SF were rescued by SCL overexpression in the antisense or dn-SCL transfectants. Furthermore, ectopic c-kit expression in as-SCL transfectants is sufficient to restore cell survival in response to SF. Finally, enforced SCL in the pro–B cell line Ba/F3, which is both SCL and c-kit negative is sufficient to induce c-Kit and SF responsiveness. Together, these results indicate that c-kit, a gene that is essential for the survival of primitive hemopoietic cells, is a downstream target of the transcription factor SCL.

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Patterning of cell assemblies regulated by adhesion receptors of the cadherin superfamily

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2000.0624 ◽

2000 ◽

Vol 355 (1399) ◽

pp. 885-890 ◽

Cited By ~ 51

Author(s):

Masatoshi Takeichi ◽

Shinichi Nakagawa ◽

Shinya Aono ◽

Tadao Usui ◽

Tadashi Uemura

Keyword(s):

Cell Adhesion ◽

Neural Tube ◽

Planar Cell Polarity ◽

Cell Types ◽

Carcinoma Cells ◽

Adhesion Receptors ◽

Cell Assemblies ◽

Cell Association ◽

Cadherin Superfamily ◽

Cell Cell

During morphogenesis, cell–cell association patterns are dynamically altered. We are interested in how cell adhesion molecules can regulate the patterning of cellular assemblies. Cadherins, a group of cell–cell adhesion receptors, are crucial for the organized assembly of many cell types, but they also regulate dynamic aspects of cell association. For example, during neural crest emigration from the neural tube, the cadherin subtypes expressed by crest cells are switched from one subtype to another. Artificial perturbation of this switch results in blocking of their escape from the neural tube. Intracellular modulations of cadherin activity also seem to play a role in regulation of cell adhesion. We identified p120 ctn as a regulator of cadherin function in carcinoma cells. With such regulators, cells may make a choice as to whether they should maintain stable cell contacts or disrupt their association. Finally, we found another type of cadherin–mediated cell patterning: Flamingo, a seven–pass transmembrane cadherin, regulates planar cell polarity in Drosophila imaginal discs. Thus, the cadherin superfamily receptors control the patterning of cell assemblies through a variety of mechanisms.

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