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103. Neuronal cells show regulatory differences in the hsp70 gene response.

Author

Kaarniranta, Kai, Oksala, Niku, Karjalainen, Hannu, Suuronen, Tiina, Sistonen, Lea, Helminen, Heikki, Salminen, Antero, Lammi, Mikko, Kaarniranta, Kai, Oksala, Niku, Karjalainen, Hannu, Suuronen, Tiina, Sistonen, Lea, Helminen, Heikki, Salminen, Antero, and Lammi, Mikko

Abstract

The synthesis of heat shock proteins (Hsps), encoded by heat shock genes, is increased in response to various stress stimuli. Hsps function as molecular chaperones, they dissociate cytotoxic stress-induced protein aggregates within cells and ensure improved survival. Induction of heat shock genes is mainly regulated at the transcriptional level. The stress responsive transcription factor, heat shock factor 1 (HSF1), is involved in the transcriptional induction of the heat shock genes. Our objective was to examine how hsp70 genes are regulated in different transformed and primary neurons upon exposure to elevated temperature. Our findings reveal that the Hsp70 response is regulated at the translational level in Neuro-2a neuroblastoma cells, while the IMR-32 neuroblastoma cells respond to stress by the classical HSF1-driven transcriptional regulatory mechanism. Primary rat hippocampal neurons show a lack of HSF1 and induction of the hsp70 gene. These observations suggest that neuronal cells display different hsp70 gene expression patterns which range from undetected response to transcriptional and posttranscriptional regulation during heat stress.

Published
2002
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108. Solustressin tutkimuksesta kliinisiin läpimurtoihin? [From research of cellular stress to various clinical break through innovations?]

Author

Kaarniranta, Kai, Oksala, Niku, Lammi, Mikko, Helminen, Heikki, Sistonen, Lea, Kaarniranta, Kai, Oksala, Niku, Lammi, Mikko, Helminen, Heikki, and Sistonen, Lea

Abstract

Fysikaalisen tai kemiallisen stressin seurauksena useiden geenien aktiivisuus vähenee,kun taas lämpösokki- eli stressigeenien induktio lisääntyy. Stressigeenit koodaavat lämpösokkiproteiineja(Hsp), jotka toimivat soluissa kaperoneina, »avustajina», auttaensolujen proteiineja laskostumaan oikein translaatiossa, kalvon läpi kuljetuksessa tai esimerkiksikorkean lämpötilan aiheuttaman vaurion jälkeen. Viime vuosina lämpösokkiproteiinienkliininen merkitys useiden sairauksien patogeneesissä, diagnostiikassa ja ennusteenmäärittämisessä on alkanut selvitä. Merkittävimmät kliiniset löydökset liittyvätiskeemisiin prosesseihin, kuten sydän- ja aivoinfarkteihin, useisiin neoplasioihin ja ikääntymiseen.Tässä katsauksessa käsittelemme stressigeenien säätelyä, Hsp70-stressiproteiinienkliinisiä yhteyksiä ja niiden mahdollisia hoitosovelluksia iskeemisissä, neoplastisissaja degeneratiivisissa prosesseissa.

Published
2001

109. Primary chondrocytes resist hydrostatic pressure-induced stress while primary synovial cells and fibroblasts show modified Hsp70 response.

Author

Kaarniranta, Kai, Holmberg, Carina, Lammi, Mikko, Eriksson, John, Sistonen, Lea, Helminen, Heikki, Kaarniranta, Kai, Holmberg, Carina, Lammi, Mikko, Eriksson, John, Sistonen, Lea, and Helminen, Heikki

Abstract

OBJECTIVE: During joint loading, chondrocytes in the articular cartilage are subjected to gradients of high compressive hydrostatic pressure (HP). In response to diverse chemical or physical stresses, heat shock genes are induced to express heat shock proteins (Hsps). This study sought to examine the role of Hsps in baroresistance in primary bovine chondrocytes and synovial cells, as well as in primary human fibroblasts. METHODS: Northern blotting was used to analyze the steady-state levels of hsp70 mRNA in the primary cells exposed to HP or heat stress. Hsp70 protein accumulation was analyzed by Western blotting, and the DNA-binding activity was examined by gel mobility shift assay. RESULTS: Primary bovine chondrocytes which have been adapted to live under pressurized conditions showed negligible Hsp70 response upon HP loading, whereas primary bovine synovial cells and human fibroblasts accumulated hsp70 mRNA and protein when subjected to HP. The response was initiated without activation of the heat shock transcription factor 1. Interestingly, pre-conditioning of the barosensitive fibroblasts with HP or heat shock reduced the Hsp70 response, indicating induction of baroresistance. CONCLUSION: This study suggests that Hsp70 can play an important role in the early stages of adaptation of cells to HP. Thus, the Hsp70 gene expression upon HP loading may serve as one indicator of the chondrocytic phenotype of the cells. This can be of use in the treatment of cartilage lesions.

Published
2001
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112. Role of heat-shock factor 2 in cerebral cortex formation and as a regulatorof p35 expression

Author

Chang, Yunhua, primary, Östling, Päivi, additional, Åkerfelt, Malin, additional, Trouillet, Diane, additional, Rallu, Murielle, additional, Gitton, Yorick, additional, El Fatimy, Rachid, additional, Fardeau, Vivienne, additional, Le Crom, Stéphane, additional, Morange, Michel, additional, Sistonen, Lea, additional, and Mezger, Valérie, additional

Published
2006
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120. Hsp70 accumulation in chondrocytic cells exposed to high continuous hydrostatic pressure coincides with mRNA stabilization rather than transcriptional activation.

Author

Kaarniranta, Kai, Elo, Mika, Sironen, Reijo, Lammi, Mikko, Goldring, Mary, Eriksson, John, Sistonen, Lea, Helminen, Heikki, Kaarniranta, Kai, Elo, Mika, Sironen, Reijo, Lammi, Mikko, Goldring, Mary, Eriksson, John, Sistonen, Lea, and Helminen, Heikki

Abstract

In response to various stress stimuli, heat shock genes are induced to express heat shock proteins (Hsps). Previous studies have revealed that expression of heat shock genes is regulated both at transcriptional and posttranscriptional level, and the rapid transcriptional induction of heat shock genes involves activation of the specific transcription factor, heat shock factor 1 (HSF1). Furthermore, the transcriptional induction can vary in intensity and kinetics in a signal- and cell-type-dependent manner. In this study, we demonstrate that mechanical loading in the form of hydrostatic pressure increases heat shock gene expression in human chondrocyte-like cells. The response to continuous high hydrostatic pressure was characterized by elevated mRNA and protein levels of Hsp70, without activation of HSF1 and transcriptional induction of hsp70 gene. The increased expression of Hsp70 was mediated through stabilization of hsp70 mRNA molecules. Interestingly, in contrast to static pressurization, cyclic hydrostatic loading did not result in the induction of heat shock genes. Our findings show that hsp70 gene expression is regulated posttranscriptionally without transcriptional induction in chondrocyte-like cells upon exposure to high continuous hydrostatic pressure. We suggest that the posttranscriptional regulation in the form of hsp70 mRNA stabilization provides an additional mode of heat shock gene regulation that is likely to be of significant importance in certain forms of stress.

Published
1998

125. Heat Shock Factor 1 as a Coordinator of Stress and Developmental Pathways.

Author

Back, Nathan, Cohen, Irun R., Kritchevsky, David, Lajtha, Abel, Paoletti, Rodolfo, Csermely, Peter, Vígh, László, Anckar, Julius, and Sistonen, Lea

Abstract

The transition from normal growth conditions to stressful conditions is accompanied by a robust upregulation of heat shock proteins, which dampen the cytotoxicity caused by misfolded and denatured proteins. The most prominent part of this transition occurs on the transcriptional level. In mammals, protein-damaging stress leads to the activation of heat shock factor 1 (HSF1), which binds to upstream regulatory sequences in the promoters of heat shock genes. The activation of HSF1 proceeds through a multi-step pathway, involving a monomer-to-trimer transition, nuclear accumulation and extensive posttranslational modifications. In addition to its established role as the main regulator of heat shock genes, new data link HSF1 to developmental pathways. In this chapter, we examine the established stress-related functions and prospect the intriguing role of HSF1 as a developmental coordinator. [ABSTRACT FROM AUTHOR]

Published
2007
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127. Regulation of the heat shock response by heat shock transcription factors.

Author

Braakman, Ineke, Hietakangas, Ville, and Sistonen, Lea

Abstract

The heat shock response is characterized by a rapid and robust increase in heat shock proteins upon exposure to protein-damaging stresses. This evolutionarily conserved cellular protection mechanism is primarily regulated at the level of transcription. In bacteria, heat shock-induced transcription is regulated by the activation of σ32 factor, whereas eukaryotes utilize heat shock transcription factors (HSFs) that bind to specific heat shock elements (HSEs) within the promoters of their target genes. Unlike yeasts, nematodes, and fruit flies, which have a single HSF, vertebrates and plants have an entire HSF family. In addition to stress-induced activation, some members of the HSF family are also activated under non-stressful conditions, including development and differentiation. The activity of HSFs is under post-translational control, requiring trimerization, DNA binding, and hyperphosphorylation. The interplay between different family members and other interacting proteins adds further complexity to HSF-mediated transcription. Here, we summarize the current knowledge of the transcriptional regulation of the heat shock response, highlighting recent advances in exploring the multi-faceted nature of heat shock transcription. [ABSTRACT FROM AUTHOR]

Published
2006
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146. Regulation of H SF1 Function in the Heat Stress Response: Implications in Aging and Disease.

Author

Anckar, Julius and Sistonen, Lea

Subjects
*HOMEOSTASIS, *PROTEINS, *HEAT shock proteins, *PEPTIDES, *TRANSCRIPTION factors
Abstract

To dampen proteotoxic stresses and maintain protein homeostasis, organisms possess a stress-responsive molecular machinery that detects and neutralizes protein damage. A prominent feature of stressed cells is the increased synthesis of heat shock proteins (Hsps) that aid in the refolding of misfolded peptides and restrain protein aggregation. Transcriptional activation of the heat shock response is orchestrated by heat shock factor 1 (HSF1), which rapidly translocates to hsp genes and induces their expression. Although the role of HSF1 in protecting cells and organisms against severe stress insults is well established, many aspects of how HSF1 senses qualitatively and quantitatively different forms of stresses have remained poorly understood. Moreover, recent discoveries that HSF1 controls life span have prompted new ways of thinking about an old transcription factor. Here, we review the established role of HSF1 in counteracting cell stress and prospect the role of HSF1 as a regulator of disease states and aging. [ABSTRACT FROM AUTHOR]

Published
2011
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147. A simple mass-action model for the eukaryotic heat shock response and its mathematical validation.

Author

Petre, Ion, Mizera, Andrzej, Hyder, Claire L., Meinander, Annika, Mikhailov, Andrey, Morimoto, Richard I., Sistonen, Lea, Eriksson, John E., and Back, Ralph-Johan

Subjects
HEAT shock proteins, MATHEMATICAL models, CELLULAR control mechanisms, ENVIRONMENTAL engineering, DEFENSE reaction (Physiology), NEURODEGENERATION, MESSENGER RNA
Abstract

The heat shock response is a primordial defense mechanism against cell stress and protein misfolding. It proceeds with the minimum number of mechanisms that any regulatory network must include, a stress-induced activation and a feedback regulation, and can thus be regarded as the archetype for a cellular regulatory process. We propose here a simple mechanistic model for the eukaryotic heat shock response, including its mathematical validation. Based on numerical predictions of the model and on its sensitivity analysis, we minimize the model by identifying the reactions with marginal contribution to the heat shock response. As the heat shock response is a very basic and conserved regulatory network, our analysis of the network provides a useful foundation for modeling strategies of more complex cellular processes. [ABSTRACT FROM AUTHOR]

Published
2011
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150. Promoter ChIP-chip analysis in mouse testis reveals Y chromosome occupancy by HSF2.

Author

Åkerfelt, Malin, Henriksson, Eva, Laiho, Asta, Vihervaara, Anniina, Rautoma, Karoliina, Kotaja, Noora, and Sistonen, Lea

Subjects
TESTIS, Y chromosome, SPERMATOZOA, CELL nuclei, CHROMATIN, ENDOCRINE glands
Abstract

The mammalian V chromosome is essential for spermatogenesis, which is characterized by sperm cell differentiation and chromatin condensation for acquisition of correct shape of the sperm. Deletions of the male-specific region of the mouse V chromosome long arm (MSYq), harboring multiple copies of a few genes, lead to sperm head defects and impaired fertility. Using chromatin immunoprecipitation on promoter microarray (ChIP-chip) on mouse testis, we found a striking in vivo MSYq occupancy by heat shock factor 2 (HSF2), a transcription factor involved in spermatogenesis. HSF2 was also found to regulate the transcription of MSYq resident genes, whose transcriptional regulation has been unknown. Importantly, disruption of Hsf2 caused a similar phenotype as the 2/3 deletion of MSVq, i.e., altered expression of the multicopy genes and increased mild sperm head abnormalities. Consequently, aberrant levels of chromatin packing proteins and more frequent DNA fragmentation were detected, implying that HSF2 is required for correct chromatin organization in the sperm. Our findings define a physiological role for HSF2 in the regulation of MSYq resident genes and the quality of sperm. [ABSTRACT FROM AUTHOR]

Published
2008
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