Anaphase-Promoting Complex/Cyclosome Participates in the Acute Response to Protein-Damaging Stress

Ahlskog, Johanna K.; Björk, Johanna; Elsing, Alexandra N.; Aspelin, Camilla; Kallio, Marko J.; Roos-Mattjus, Pia; Sistonen, Lea

doi:10.1128/mcb.01506-09

Cited by 39 publications

(56 citation statements)

References 107 publications

(154 reference statements)

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“…(A) HSF1 and HSF2 protein levels during the 2-h heat stress in scrambled-transfected (Scr), HSF1-depleted (shHSF1), and HSF2-depleted (shHSF2) cycling cells. HSF2 levels decline on heat stress as previously reported (25). (B) mRNA levels of chaperones HSPH1, HSPH2, DNAJB6, and chaperonin CCT1 during heat stress in the presence or absence of HSF1 or HSF2.…”

Section: Resultssupporting

confidence: 74%

“…Our preliminary results show an HSF2-mediated effect on transcription during prolonged stress when HSF2 levels have already declined (Fig. S4F) (25) and suggest that HSF2 modifies the chromatin landscape for transcriptional responses. HSF2 is also involved in many developmental processes when the epigenetic features of the cells are determined (10,12,61), and it has been shown to affect the chromatin compaction and integrity (10).…”

Section: Discussionmentioning

confidence: 64%

“…2-4). HSF1 and HSF2 show similar recruitment kinetics to the HSP70 promoter, but HSF2 is gradually degraded from the HSE after 30 min of heat stress (25), indicating the need for delicate regulation of the HSF1-HSF2 composition at the promoter. Our preliminary results show an HSF2-mediated effect on transcription during prolonged stress when HSF2 levels have already declined (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…However, the previous studies have almost exclusively concentrated on the expression of a handful of HSP genes in unsynchronized cell populations (17,(25)(26)(27)(28). Currently, comprehensive knowledge on the target genes for HSF1 and HSF2 and their cooperation during stress responses is missing.…”

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confidence: 99%

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Transcriptional response to stress in the dynamic chromatin environment of cycling and mitotic cells

Vihervaara

Sergelius

Vasara

et al. 2013

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

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141

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Heat shock factors (HSFs) are the master regulators of transcription under protein-damaging conditions, acting in an environment where the overall transcription is silenced. We determined the genomewide transcriptional program that is rapidly provoked by HSF1 and HSF2 under acute stress in human cells. Our results revealed the molecular mechanisms that maintain cellular homeostasis, including HSF1-driven induction of polyubiquitin genes, as well as HSF1-and HSF2-mediated expression patterns of cochaperones, transcriptional regulators, and signaling molecules. We characterized the genomewide transcriptional response to stress also in mitotic cells where the chromatin is tightly compacted. We found a radically limited binding and transactivating capacity of HSF1, leaving mitotic cells highly susceptible to proteotoxicity. In contrast, HSF2 occupied hundreds of loci in the mitotic cells and localized to the condensed chromatin also in meiosis. These results highlight the importance of the cell cycle phase in transcriptional responses and identify the specific mechanisms for HSF1 and HSF2 in transcriptional orchestration. Moreover, we propose that HSF2 is an epigenetic regulator directing transcription throughout cell cycle progression.ChIP-seq | ENCODE | human genome | proteostasis C ells exposed to proteotoxic conditions provoke a rapid and transient response to maintain homeostasis. The stress response induces profound cellular adaptation as cytoskeleton and membranes are reorganized, cell cycle progression is stalled, and the global transcription and translation are silenced (1, 2). Despite the silenced chromatin environment, the stressed cell mounts a transcriptional program that involves induction of genes coding for heat shock proteins (HSPs). HSPs are molecular chaperones and proteases that assist in protein folding and maintain cellular structures and molecular functions (3).Heat shock factor 1 (HSF1) is an evolutionarily well-conserved transcription factor that is rapidly activated by stress and absolutely required for the stress-induced HSP expression (4). Aberrant HSF1 levels are associated with stress sensitivity, aging, neurodegenerative diseases, and cancer (5-9). Instead of a single HSF in yeasts and invertebrates, vertebrates contain a family of four members, HSF1-4. HSF2 and HSF4 are involved in corticogenesis, spermatogenesis, and formation of sensory epithelium, and they have primarily been considered as developmental factors (10-14). HSF1 and HSF2 share high sequence homology of the DNA-binding and oligomerization domains and are able to form heterotrimers at the chromatin (15, 16). Moreover, HSF2 participates in the regulation of stress-responsive genes and is required for proper protein clearance also at febrile temperatures (17,18). Although HSF1 and HSF2 have been shown to interplay on the heat shock elements (HSEs) of the target loci, their impacts on transcription of chaperone genes are remarkably different; HSF1 is a potent inducer of transcription, whereas HSF2 is a poor transactivator o...

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Section: Resultssupporting

confidence: 74%

Section: Discussionmentioning

confidence: 64%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Transcriptional response to stress in the dynamic chromatin environment of cycling and mitotic cells

Vihervaara

Sergelius

Vasara

et al. 2013

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

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141

177

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“…This finding is in agreement with a recent study showing that HSF1 phosphorylation does not affect its turnover (32). In order to validate that protein translation was inhibited by CHX, we analyzed the protein levels of HSF2 which is known to have a fast turnover rate (60,61). As expected, HSF2 was rapidly degraded and not detectable after a 3-h CHX treatment (Fig.…”

Section: Hsf1⌬ϳprd and Hsf1supporting

confidence: 76%

Uncoupling Stress-Inducible Phosphorylation of Heat Shock Factor 1 from Its Activation

Budzyński

Puustinen

Joutsen

et al. 2015

Molecular and Cellular Biology

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bIn mammals the stress-inducible expression of genes encoding heat shock proteins is under the control of the heat shock transcription factor 1 (HSF1). Activation of HSF1 is a multistep process, involving trimerization, acquisition of DNA-binding and transcriptional activities, which coincide with several posttranslational modifications. Stress-inducible phosphorylation of HSF1, or hyperphosphorylation, which occurs mainly within the regulatory domain (RD), has been proposed as a requirement for HSF-driven transcription and is widely used for assessing HSF1 activation. Nonetheless, the contribution of hyperphosphorylation to the activity of HSF1 remains unknown. In this study, we generated a phosphorylation-deficient HSF1 mutant (HSF1⌬ϳPRD), where the 15 known phosphorylation sites within the RD were disrupted. Our results show that the phosphorylation status of the RD does not affect the subcellular localization and DNA-binding activity of HSF1. Surprisingly, under stress conditions, HSF1⌬ϳPRD is a potent transactivator of both endogenous targets and a reporter gene, and HSF1⌬ϳPRD has a reduced activation threshold. Our results provide the first direct evidence for uncoupling stress-inducible phosphorylation of HSF1 from its activation, and we propose that the phosphorylation signature alone is not an appropriate marker for HSF1 activity.T he heat shock response, as characterized by inducible expression of heat shock proteins (Hsps), is an ancient, evolutionarily conserved mechanism that protects cells from various proteotoxic insults, including exposures to elevated temperatures, heavy metals, proteasome inhibition, and oxidative stress (1). Hsps function as molecular chaperones, bind to misfolded proteins, facilitate their refolding or direct them to degradation, and block the formation of protein aggregates (2, 3). The heat shock response is controlled by heat shock transcription factors (HSFs) (4). In vertebrates, four HSFs (HSF1 to HSF4) have been found, whereas yeasts, flies, and nematodes have only a single HSF. HSFs bind DNA at evolutionarily well-conserved sequences, consisting of inverted nGAAn repeats, called heat shock elements (5-8). HSF1 is considered the master regulator of the heat shock response in mammals, since mice lacking HSF1 are unable to induce Hsp expression upon exposure to protein-damaging stress (9, 10). Besides controlling the stress-inducible expression of Hsps, HSF1 plays a role in development (10-12), life span regulation (13-15), immune responses (16), and the circadian cycle (17). In addition, HSF1 is a well-recognized transcriptional regulator in malignant human cancers (18)(19)(20).The HSF1 protein is composed of five distinguishable functional domains (see Fig. 1A). The DNA-binding domain (DBD) is located at the N terminus (21), whereas the transactivation domain (TAD) resides in the C terminus (22). A unique requirement for HSF1 activation is the process of trimerization through an intermolecular interaction of leucine-zipper-like heptad repeat domains (HR-A/B) between HSF1...

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The Role of Heat Shock Factors in Mammalian Spermatogenesis

Widłak

Vydra

2017

Advances in Anatomy, Embryology and Cell Biology

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Heat shock transcription factors (HSFs), as regulators of heat shock proteins (HSPs) expression, are well known for their cytoprotective functions during cellular stress. They also play important yet less recognized roles in gametogenesis. All HSF family members are expressed during mammalian spermatogenesis, mainly in spermatocytes and round spermatids which are characterized by extensive chromatin remodeling. Different HSFs could cooperate to maintain proper spermatogenesis. Cooperation of HSF1 and HSF2 is especially well established since their double knockout results in meiosis arrest, spermatocyte apoptosis, and male infertility. Both factors are also involved in the repackaging of the DNA during spermatid differentiation. They can form heterotrimers regulating the basal level of transcription of target genes. Moreover, HSF1/HSF2 interactions are lost in elevated temperatures which can impair the transcription of genes essential for spermatogenesis. In most mammals, spermatogenesis occurs a few degrees below the body temperature and spermatogenic cells are extremely heat-sensitive. Pro-survival pathways are not induced by heat stress (e.g., cryptorchidism) in meiotic and postmeiotic cells. Instead, male germ cells are actively eliminated by apoptosis, which prevents transition of the potentially damaged genetic material to the next generation. Such a response depends on the transcriptional activity of HSF1 which in contrary to most somatic cells, acts as a proapoptotic factor in spermatogenic cells. HSF1 activation could be the main trigger of impaired spermatogenesis related not only to elevated temperature but also to other stress conditions; therefore, HSF1 has been proposed to be the quality control factor in male germ cells.

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Anaphase-Promoting Complex/Cyclosome Participates in the Acute Response to Protein-Damaging Stress

Cited by 39 publications

References 107 publications

Transcriptional response to stress in the dynamic chromatin environment of cycling and mitotic cells

Transcriptional response to stress in the dynamic chromatin environment of cycling and mitotic cells

Uncoupling Stress-Inducible Phosphorylation of Heat Shock Factor 1 from Its Activation

The Role of Heat Shock Factors in Mammalian Spermatogenesis

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