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Full-Text Articles in Biochemistry, Biophysics, and Structural Biology
Hsp70-Mediated Regulation Of Hsf1 Transcriptional Activity In Saccharomyces Cerevisiae, Sara Peffer
Hsp70-Mediated Regulation Of Hsf1 Transcriptional Activity In Saccharomyces Cerevisiae, Sara Peffer
Dissertations & Theses (Open Access)
In eukaryotic cells, protein homeostasis and cellular fitness is promoted by the transcription factor heat shock factor 1 (HSF1) during exposure to proteotoxic stress. HSF1 controls the basal and stress-induced expression of molecular chaperones and other protective targets. Dynamic regulation of HSF1 involves the major heat shock proteins Hsp70 and Hsp90. Recent advances in the understanding of this regulatory circuit in Saccharomyces cerevisiae have shown that the Hsp70 Ssa1 acts as a sensor for some proteotoxic stresses and is capable of a direct interaction with Hsf1. This work continues to explore the complex regulatory interaction between Hsf1 and Ssa1. I …
Functional Analysis Of Cytosolic Hsp70 Nucleotide Exchange Factor Networks In Yeast, Jennifer Lynn Abrams
Functional Analysis Of Cytosolic Hsp70 Nucleotide Exchange Factor Networks In Yeast, Jennifer Lynn Abrams
Dissertations & Theses (Open Access)
The Hsp70 class of molecular chaperones play critical roles in protein homeostasis via an ATP-dependent folding cycle. Cytosolic Hsp70s in the budding yeast Saccharomyces cerevisiae, Ssa and Ssb, interact with up to three distinct nucleotide exchange factors (NEFs) homologous to human counterparts; Sse1/Sse2/HSP110, Fes1/HspBP1, and Snl1/Bag1. In an effort to understand the differential functional contributions of the cytosolic NEFs to protein homeostasis (“proteostasis”), I carried out comparative genetic, biochemical and cell biological analyses. For these studies, I developed protocols to monitor protein disaggregation and reactivation in a near real-time coupled assay that revealed the importance of aggregate dynamics in the …
Mechanisms Underlying The Heterogeneous Sensitivities Of Cancer Cells To Proteasome Inhibitors, Matthew C. White
Mechanisms Underlying The Heterogeneous Sensitivities Of Cancer Cells To Proteasome Inhibitors, Matthew C. White
Dissertations & Theses (Open Access)
The mechanisms underlying cellular response to proteasome inhibitors have not been clearly elucidated in solid tumor models. Evidence suggests that the ability of a cell to manage the amount of proteotoxic stress following proteasome inhibition dictates survival. In this study using the FDA-approved proteasome inhibitor bortezomib (Velcade®) in solid tumor cells, we demonstrated that perhaps the most critical response to proteasome inhibition is repression of global protein synthesis by phosphorylation of the eukaryotic initiation factor 2-α subunit (eIF2α). In a panel of 10 distinct human pancreatic cancer cells, we showed marked heterogeneity in the ability of cancer cells to induce …