Spermatocyte-specific expression of constitutively active heat shock factor 1 induces HSP70i-resistant apoptosis in male germ cells

Vydra, Natalia; Małusecka, Ewa; Jarząb, Michał; Lisowska, Katarzyna; Głowala-Kosińska, Magdalena; Benedyk, Konrad; Widłak, Piotr; Krawczyk, Z; Widłak, Wiesława

doi:10.1038/sj.cdd.4401758

Cited by 50 publications

(72 citation statements)

References 64 publications

(60 reference statements)

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“…By contrast, a pro-apoptotic role for the Hsp system has been reported in spermatocytes from mice expressing a constitutively active form of HSF1 that undergo mitochondrialdependent apoptosis, mimicking heat shock-induced death of spermatogenic cells (57). A strengthening role of heat shock has also been suggested to be operative in TRAIL-induced apoptosis of transformed T lymphocytes, although it does not seem to be ascribed to Hsp neosynthesis (39).…”

Section: Redox-responsive Anti-apoptotic Proteins: Key Components Of mentioning

confidence: 99%

Redox Control of Apoptosis: An Update

Filomeni

Ciriolo

2006

Antioxidants & Redox Signaling

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The redox environment of the cell is currently thought to be extremely important to control cell growth, differentiation, and apoptosis as many redox-sensitive proteins characterize these networks. A recent, widely accepted theory is that free radicals are not only dangerous species but, at low concentration, they have been designed by evolution to participate in the maintenance of cellular redox (reduction/oxidation) homeostasis. This notion derives from the evidence that cells constantly generate free radicals both as waste products of aerobic metabolism and in response to a large variety of stimuli. Free radicals, once produced, provoked cellular responses (redox regulation) against oxidative stress transducing the signals to maintain the cellular redox balance. Growing evidence suggests that in many instances the production of radical species is tightly regulated and their downstream targets are very specific, indicating that reactive oxygen species and reactive nitrogen species actively participate in several cell-signalling pathways as physiological "second messengers." In this review, we provide a general overview and novel insights into the redox-dependent pathways involved in programmed cell death.

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Section: Redox-responsive Anti-apoptotic Proteins: Key Components Of mentioning

confidence: 99%

Redox Control of Apoptosis: An Update

Filomeni

Ciriolo

2006

Antioxidants & Redox Signaling

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“…Increasing the temperature of testis up to the body temperature (or above it) leads to the activation of HSF1. However, inducible Hspa1 (Hsp70i) genes expression is blocked in heat shocked murine spermatocytes (Izu et al, 2004;Vydra et al, 2006), although HSF1 binds to their promoters (Kus-Liśkiewicz et al, 2013). Moreover, the constitutively expressed testis-specific variant of HSP70 (HSPA2) is depleted after HSF1 activation (Widlak et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Crosstalk between HSF1 and HSF2 during the heat shock response in mouse testes

Korfanty

Stokowy

Widłak

et al. 2014

The International Journal of Biochemistry & Cell Biology

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Heat Shock Factor 1 (HSF1) is the primary transcription factor responsible for the response to cellular stress, while HSF2 becomes activated during development and differentiation, including spermatogenesis. Although both factors are indispensable for proper spermatogenesis, activation of HSF1 by heat shock initiates apoptosis of spermatogenic cells leading to infertility of males. To characterize mechanisms assisting such heat induced apoptosis we studied how HSF1 and HSF2 cooperate during the heat shock response. For this purpose we used chromatin immunoprecipitation and the proximity ligation approaches. We looked for co-occupation of binding sites by HSF1 and HSF2 in untreated (32 °C) or heat shocked (at 38 °C or 43 °C) spermatocytes, which are cells the most sensitive to hyperthermia. At the physiological temperature or after mild hyperthermia at 38 °C, the sharing of binding sites for both HSFs was observed mainly in promoters of Hsp genes and other stress-related genes. Strong hyperthermia at 43 °C resulted in an increased binding of HSF1 and releasing of HSF2, hence co-occupation of promoter regions was not detected any more. The close proximity of HSF1 and HSF2 (and/or existence of HSF1/HSF2 complexes) was frequent at the physiological temperature. Temperature elevation resulted in a decreased number of such complexes and they were barely detected after strong hyperthermia at 43 °C. We have concluded that at the physiological temperature HSF1 and HSF2 cooperate in spermatogenic cells. However, temperature elevation causes remodeling of chromatin binding and interactions between HSFs are disrupted. This potentially affects the regulation of stress response and contributes to the heat sensitivity of these cells.

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“…An intriguing congruency has been reported during meiotic division in mouse spermatocytes, where HSF1 was shown to bind to the exogenous HSE on heat stress but no binding to the HSP70 promoter could be detected (11,(58)(59)(60). Because HSF2-deficient mice display meiotic defects (61), we investigated by confocal microscopy the subcellular localization of HSF1 and HSF2 in metaphase spermatocytes.…”

Section: Mitosis Inhibits Transcriptional Activation and Renders Chromentioning

confidence: 99%

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.

135

177

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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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Spermatocyte-specific expression of constitutively active heat shock factor 1 induces HSP70i-resistant apoptosis in male germ cells

Cited by 50 publications

References 64 publications

Redox Control of Apoptosis: An Update

Redox Control of Apoptosis: An Update

Crosstalk between HSF1 and HSF2 during the heat shock response in mouse testes

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

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