Antimyeloma Effects of the Heat Shock Protein 70 Molecular Chaperone Inhibitor MAL3-101

Multiple myeloma (MM) is the second most common hematologic malignancy and remains incurable, primarily due to the treatment-refractory/resistant nature of the disease. A rational approach to this compelling challenge is to develop new drugs that act synergistically with existing effective agents. This approach will reduce drug concentrations, avoid treatment resistance, and also improve treatment effectiveness by targeting new and nonredundant pathways in MM. Toward this goal, we examined the antimyeloma effects of MAL3-101, a member of a new class of non-ATP-site inhibitors of the heat shock protein (Hsp) 70 molecular chaperone. We discovered that MAL3-101 exhibited antimyeloma effects on MM cell lines in vitro and in vivo in a xenograft plasmacytoma model, as well as on primary tumor cells and bone marrow endothelial cells from myeloma patients. In combination with a proteasome inhibitor, MAL3-101 significantly potentiated the in vitro and in vivo antimyeloma effects. These data support a preclinical rationale for small molecule inhibition of Hsp70 function, either alone or in combination with other agents, as an effective therapeutic strategy for MM

A CHOP-regulated microRNA controls rhodopsin expression

ER stress induces expression of miR-708, which suppresses the production of rhodopsin to prevent ER overloading in retinal epithelial cells

The ER Stress-dependent Regulation of MicroRNAs in Mammals

MicroRNAs (miRNAs) are small, non-coding RNAs that post-transcriptionally regulate messenger RNAs through sequence-specific interactions. miRNAs have recently been shown to exert their regulatory influence during cellular stresses. Endoplasmic reticulum (ER) stress, one example of a cellular stress, stems from an imbalance in the ER's protein folding capacity, oftentimes resulting from such insults as an increase in protein load or expression of misfolding mutant proteins. Consequently, mis- or unfolded proteins accumulate within the ER, which triggers the unfolded protein response (UPR). In mammals, three UPR sensors, IRE1, ATF6, and PERK, detect the folding status of the ER, thus activating transcriptional as well as post-transcriptional programs that lead to adaptation. If ER stress is unmitigated and homeostasis is not restored, the UPR switches from a cytoprotective role to an apoptotic one. Intriguingly, genome-wide miRNA expression analyses revealed a more complex downstream adaptive network of the UPR. Prolonged ER stress prompted the differential regulation of 11 miRNAs, 8 of which were up-regulated in the presence of ER stress-inducing drugs. The differential expression of only one of those miRNAs, miR-708, demonstrated a dependence on the UPR transcription factor, CHOP. Curiously, mir-708 resides in the intron of Odz4, a gene ambiguously involved in neural development that was also previously characterized as transcriptionally activated by CHOP. The striking co-expression of both miR-708 and Odz4 in the brain and eyes suggested a common physiological function in these tissues. Furthermore, loss- and gain-of-function experiments showed that miR-708 inhibits the expression of rhodopsin, a heavily synthesized multi-spanning transmembrane protein in photoreceptor cells of the eye. In light of this, one can speculate a cytoprotective role for miR-708 whereby it acts to prevent excessive rhodopsin from entering the ER in photoreceptor cell. Thus, miR-708 and its transcriptional activator, CHOP, are implicated in the homeostatic regulation of ER function in the mammalian visual system

The ER Stress-dependent Regulation of MicroRNAs in Mammals

MicroRNAs (miRNAs) are small, non-coding RNAs that post-transcriptionally regulate messenger RNAs through sequence-specific interactions. miRNAs have recently been shown to exert their regulatory influence during cellular stresses. Endoplasmic reticulum (ER) stress, one example of a cellular stress, stems from an imbalance in the ER's protein folding capacity, oftentimes resulting from such insults as an increase in protein load or expression of misfolding mutant proteins. Consequently, mis- or unfolded proteins accumulate within the ER, which triggers the unfolded protein response (UPR). In mammals, three UPR sensors, IRE1, ATF6, and PERK, detect the folding status of the ER, thus activating transcriptional as well as post-transcriptional programs that lead to adaptation. If ER stress is unmitigated and homeostasis is not restored, the UPR switches from a cytoprotective role to an apoptotic one. Intriguingly, genome-wide miRNA expression analyses revealed a more complex downstream adaptive network of the UPR. Prolonged ER stress prompted the differential regulation of 11 miRNAs, 8 of which were up-regulated in the presence of ER stress-inducing drugs. The differential expression of only one of those miRNAs, miR-708, demonstrated a dependence on the UPR transcription factor, CHOP. Curiously, mir-708 resides in the intron of Odz4, a gene ambiguously involved in neural development that was also previously characterized as transcriptionally activated by CHOP. The striking co-expression of both miR-708 and Odz4 in the brain and eyes suggested a common physiological function in these tissues. Furthermore, loss- and gain-of-function experiments showed that miR-708 inhibits the expression of rhodopsin, a heavily synthesized multi-spanning transmembrane protein in photoreceptor cells of the eye. In light of this, one can speculate a cytoprotective role for miR-708 whereby it acts to prevent excessive rhodopsin from entering the ER in photoreceptor cell. Thus, miR-708 and its transcriptional activator, CHOP, are implicated in the homeostatic regulation of ER function in the mammalian visual system

Bridging gaps in traditional research training with iBiology Courses.

iBiology Courses provide trainees with just-in-time learning resources to become effective researchers. These courses can help scientists build core research skills, plan their research projects and careers, and learn from scientists with diverse backgrounds

Bridging gaps in traditional research training with iBiology Courses.

iBiology Courses provide trainees with just-in-time learning resources to become effective researchers. These courses can help scientists build core research skills, plan their research projects and careers, and learn from scientists with diverse backgrounds

Benefits for participants who have taken iBiology Courses.

Benefits for participants who have taken iBiology Courses.</p

Elements of iBiology Courses that contribute to student learning and meaningful interactions with mentors.

(01) The course lessons contain different modalities, such as videos and interactive prompts, designed to engage diverse learners and deepen their skills and knowledge. (02) By answering a series of reflective prompts throughout the course, participants create tangible plans that outline their goals, approaches, and anticipated outcomes relevant to the skills they want to develop in the lab. In each course, participants are directed to share their plans with mentors to receive feedback and guidance. (03) The courses include several ways for participants to personalize their own learning. (04) The most helpful learning components as identified by participants in surveys. BCLS, Business Concepts for Life Scientists; LE, Let’s Experiment; PYSJ, Planning Your Scientific Journey; SYR, Share Your Research.</p