A5067359095- Heat shock proteins research
- Genetics, Aging, and Longevity in Model Organisms
- Endoplasmic Reticulum Stress and Disease
- Telomeres, Telomerase, and Senescence
- Cell death mechanisms and regulation
- Protein Structure and Dynamics
- Mitochondrial Function and Pathology
- ATP Synthase and ATPases Research
- thermodynamics and calorimetric analyses
- Cancer Research and Treatments
- Cancer-related Molecular Pathways
- Computational Drug Discovery Methods
- Immunotherapy and Immune Responses
- Autophagy in Disease and Therapy
- RNA Interference and Gene Delivery
- Virus-based gene therapy research
- DNA Repair Mechanisms
- Adipose Tissue and Metabolism
- Bone Metabolism and Diseases
- Insect and Pesticide Research
- Enzyme Structure and Function
- Healthcare and Venom Research
- Photoreceptor and optogenetics research
- Spaceflight effects on biology
- RNA Research and Splicing
CURE International UK
2019-2024
AVEO Oncology (United States)
2024
Boston University
2010-2023
University School
2014-2019
Boston Biomedical Research Institute
1997-2001
Medical Radiological Research Center
1993-2000
Russian Academy of Sciences
1997
Academy of Medical Sciences
1993-1994
Lomonosov Moscow State University
1982-1985
Harmful conditions including heat shock, oxidative stress, UV, and so forth cause programmed cell death, whose triggering requires activation of the Jun N-terminal kinase, JNK. High levels Hsp72, a heat-inducible member Hsp70 family, protect cells against variety stresses by mechanism that is unclear at present. Here we report elevated Hsp72 inhibit signal transduction pathway leading to death preventing stress-induced Stress-induced another stress-kinase, p38 (HOG1), also blocked when level...
Inhibition of the major cytosolic protease, proteasome, has been reported to induce programmed cell death in several lines, while with other similar inhibition blocked apoptosis triggered by a variety harmful treatments. To elucidate mechanism pro- and antiapoptotic action proteasome inhibitors, their effects on U937 lymphoid 293 kidney human tumor cells were tested. Treatment peptidyl aldehyde MG132 inhibitors led steady increase activity c-Jun N-terminal kinase, JNK1, which is known...
Various stresses activate the c-Jun N-terminal kinase (JNK), which is involved in regulation of many aspects cellular physiology, including apoptosis. Here we demonstrate that contrast to UV irradiation, heat shock causes little or no stimulation JNK-activating SEK1, while knocking out SEK1 gene completely blocks heat-induced JNK activation. Therefore, tested whether activates via inhibition dephosphorylation. The rate dephosphorylation unstimulated cells was high, and exposure osmotic...
Bag3, a nucleotide exchange factor of the heat shock protein Hsp70, has been implicated in cell signaling. Here, we report that Bag3 interacts with SH3 domain Src, thereby mediating effects Hsp70 on Src Using several complementary approaches, established Hsp70-Bag3 module is broad-acting regulator cancer signaling by modulating activity transcription factors NF-κB, FoxM1, Hif1α, translation HuR, and cell-cycle regulators p21 survivin. We also identified small-molecule inhibitor, YM-1,...
AbstractThe major inducible heat shock protein Hsp72 has been shown to protect cells from certain apoptotic stimuli. Here we investigated the mechanism of Hsp72-mediated protection tumor necrosis factor (TNF)-induced apoptosis primary culture IMR90 human fibroblasts. temporarily blocked in response TNF and permanently protected shock. An mutant (Hsp72ΔEEVD) with a deletion four C-terminal amino acids, which are essential for chaperone function, TNF-induced manner similar that normal but did...
Pretreatment with mild heat shock is known to protect cells from severe stress (acquired thermotolerance). Here we addressed the mechanism of this phenomenon by using primary human fibroblasts. Severe (45 degrees C, 75 min) fibroblasts caused cell death displaying morphological characteristics apoptosis; however, it was caspase independent. This process accompanied strong activation Akt, extracellular signal-regulated kinase 1 (ERK1) and ERK2, p38, c-Jun N-terminal (JNK) kinases. Suppression...
Abstract Novel classes of anticancer drugs, including proteasome inhibitors and Hsp90 inhibitors, potently induce heat shock proteins (Hsps). Because Hsps show antiapoptotic activities, we suggested that suppression such induction may sensitize cancer cells to these drugs. Here, knocked out the major transcription factor HSF-1 in several cell lines using small interfering RNA showed cells, which can no longer response become more sensitive Furthermore, developed a high-throughput screen for...
Abstract The small heat shock protein Hsp27 is expressed at high levels in many tumors and provides protection against anticancer drugs. Here, we show that expression of recombinant elevated leads to MCF10A human mammary epithelial cells from doxorubicin. was associated with suppression the doxorubicin-induced senescence, where inhibited p53-mediated induction p21, major regulator senescence program. Similarly, accumulation p21 suppressed response p53 activator nutlin-3, indicating has a...
Although hsp70 antagonizes apoptosis-inducing factor (AIF)-mediated cell death, the relative importance of preventing its release from mitochondria versus sequestering leaked AIF in cytosol remains controversial. To dissect these two protective mechanisms, deletion mutants lacking either chaperone function (hsp70-deltaEEVD) or ATPase (hsp70-deltaATPase) were selectively overexpressed before exposing cells to a metabolic inhibitor, an insult sufficient cause mitochondrial release, nuclear...
Abstract The major heat shock protein Hsp72 is constitutively expressed in many tumor cell lines and biopsies, its expression correlates with poor prognosis several types of cancer. was suggested to play an important role neoplastic transformation development. We addressed the cancer cells by investigating consequences specific depletion using small interfering RNA. Down-regulation certain triggered senescence associated activation stabilization p53 induction cycle inhibitor p21. Effects on...
The heat shock protein Hsp72 is expressed at the elevated levels in various human tumors, and its often correlate with poor prognosis.Previously we reported that knockdown of certain cancer cells, but not untransformed breast epithelial triggers senescence via p53-dependent p53-independent mechanisms.Here demonstrate pathway controlled by depends on oncogenic form phosphatidylinositol 3-kinase (PI3K).Indeed, upon expression PI3K, cells began responding to depletion activating p53...
Previously we demonstrated that the heat shock transcription factor Hsf1 is indispensable for transformation of mammary epithelial cells by Her2 oncogene. Since affects oncogene-induced senescence (OIS), these findings suggest tumor initiation when OIS plays a role. Indeed, here report knockout suppressed hyperplasia in Her2-expressing mice and reduced emergence. On other hand, expression increases with advanced breast cancer, indicating there an additional role progression. We studied rare...
Ubiquitinated proteins aggregate upon proteasome failure, and the aggregates are transported to aggresome. In aggresomes, protein actively degraded by autophagy-lysosome pathway, but why targeting aggresome promotes degradation of aggregated species is currently unknown. Here we report that important factor in this process clustering lysosomes around via a novel mechanism. Proteasome inhibition causes formation zone centrosome where microtubular transport suppressed, resulting their...
Since protection of cells from stress-induced apoptosis by the heat shock protein Hsp72 involves suppression stress kinase JNK, we suggested that Hsp72-mediated JNK inhibition might also be critical for myocardial ischemia/reperfusion. Transient energy deprivation H9c2 myogenic cells, used as an in vitro model ischemia, led to cell death had morphological features and necrosis was independent caspases. Surprisingly, this unusual type regulated ERK kinases. In fact, specific increased...
Abnormal polypeptides that escape proteasome-dependent degradation and aggregate in cytosol can be transported via microtubules to an aggresome, a recently discovered organelle where aggregated proteins are stored or degraded by autophagy. We used synphilin 1, protein implicated Parkinson disease, as model study mechanisms of aggresome formation. When expressed naïve HEK293 cells, 1 forms multiple small highly mobile aggregates. However, proteasome Hsp90 inhibition rapidly triggered their...