scholarly journals Molecular Mechanisms of the Teratogenic Effects of Thalidomide

2020 ◽  
Vol 13 (5) ◽  
pp. 95 ◽  
Author(s):  
Tomoko Asatsuma-Okumura ◽  
Takumi Ito ◽  
Hiroshi Handa
Keyword(s):  
Multiple Myeloma ◽  
Transcription Factor ◽  
Adverse Effects ◽  
Molecular Mechanisms ◽  
Therapeutic Effects ◽  
Teratogenic Effects ◽  
Ring E3 Ligase ◽  
Direct Target ◽  
Transcription Factor 4 ◽  
Ring E3

Thalidomide was sold worldwide as a sedative over 60 years ago, but it was quickly withdrawn from the market due to its teratogenic effects. Thalidomide was later found to have therapeutic effects in several diseases, although the molecular mechanisms remained unclear. The discovery of cereblon (CRBN), the direct target of thalidomide, a decade ago greatly improved our understanding of its mechanism of action. Accumulating evidence has shown that CRBN functions as a substrate of Cullin RING E3 ligase (CRL4CRBN), whose specificity is controlled by ligands such as thalidomide. For example, lenalidomide and pomalidomide, well-known thalidomide derivatives, degrade the neosubstrates Ikaros and Aiolos, resulting in anti-proliferative effects in multiple myeloma. Recently, novel CRBN-binding drugs have been developed. However, for the safe handling of thalidomide and its derivatives, a greater understanding of the mechanisms of its adverse effects is required. The teratogenic effects of thalidomide occur in multiple tissues in the developing fetus and vary in phenotype, making it difficult to clarify this issue. Recently, several CRBN neosubstrates (e.g., SALL4 (Spalt Like Transcription Factor 4) and p63 (Tumor Protein P63)) have been identified as candidate mediators of thalidomide teratogenicity. In this review, we describe the current understanding of molecular mechanisms of thalidomide, particularly in the context of its teratogenicity.

scholarly journals Non-Hematologic Toxicity of Bortezomib in Multiple Myeloma: The Neuromuscular and Cardiovascular Adverse Effects

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2540 ◽  
Author(s):  
Elia Pancheri ◽  
Valeria Guglielmi ◽  
Grzegorz M. Wilczynski ◽  
Manuela Malatesta ◽  
Paola Tonin ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Multiple Myeloma ◽  
Adverse Effects ◽  
Molecular Mechanisms ◽  
Proteasome Inhibitors ◽  
Hematologic Toxicity ◽  
Negative Effects ◽  
Early Discontinuation ◽  
Cardiovascular Side Effects

The overall approach to the treatment of multiple myeloma (MM) has undergone several changes during the past decade. and proteasome inhibitors (PIs) including bortezomib, carfilzomib, and ixazomib have considerably improved the outcomes in affected patients. The first-in-class selective PI bortezomib has been initially approved for the refractory forms of the disease but has now become, in combination with other drugs, the backbone of the frontline therapy for newly diagnosed MM patients, as well as in the maintenance therapy and relapsed/refractory setting. Despite being among the most widely used and highly effective agents for MM, bortezomib can induce adverse events that potentially lead to early discontinuation of the therapy with negative effects on the quality of life and outcome of the patients. Although peripheral neuropathy and myelosuppression have been recognized as the most relevant bortezomib-related adverse effects, cardiac and skeletal muscle toxicities are relatively common in MM treated patients, but they have received much less attention. Here we review the neuromuscular and cardiovascular side effects of bortezomib. focusing on the molecular mechanisms underlying its toxicity. We also discuss our preliminary data on the effects of bortezomib on skeletal muscle tissue in mice receiving the drug.

Nicotinamide N-methyltransferase (NNMT) upregulation via the mTORC1-ATF4 pathway activation contributes to palmitate-induced lipotoxicity in hepatocytes

2021 ◽  
Author(s):  
Alexandra Griffiths ◽  
Jun Wang ◽  
Qing Song ◽  
Iredia D. Iyamu ◽  
Lifeng Liu ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Molecular Mechanisms ◽  
Alcoholic Fatty Liver ◽  
Unfolded Protein ◽  
Activating Transcription Factor 4 ◽  
Pathway Activation ◽  
Hepatic Lipotoxicity ◽  
Activating Transcription Factor ◽  
Protein Response ◽  
Transcription Factor 4

Defined as the dysfunction and/or cell death caused by toxic lipids accumulation in hepatocytes, hepatic lipotoxicity plays a pathological role in non-alcoholic fatty liver disease. The cellular and molecular mechanisms underlying lipotoxicity remain to be elucidated. In this study, using AML12 cells, a non-transformed murine hepatocyte cell line, exposed to palmitate (a 16-C saturated fatty acid) as an experimental model, we investigated the role and mechanisms of nicotinamide N-methyltransferase (NNMT), a methyltransferase catalyzing nicotinamide methylation and degradation, in hepatic lipotoxicity. We initially identified activating transcription factor 4 (ATF4) as a major transcription factor for hepatic NNMT expression. Here, we demonstrated that palmitate upregulates NNMT expression via activating ATF4 in a mechanistic target of rapamycin complex 1 (mTORC1)-dependent mechanism in that mTORC1 inhibition by both Torin1 and rapamycin attenuated ATF4 activation and NNMT upregulation. We further demonstrated that the mTORC1-dependent ATF4 activation is an integral signaling event of unfolded protein response (UPR) as both ATF4 activation and NNMT upregulation by tunicamycin, a well-documented endoplasmic reticulum (ER) stress inducer, are blunted when hepatocytes were pretreated with Torin1. Importantly, our data uncovered that NNMT upregulation contributes to palmitate-induced hepatotoxicity as NNMT inhibition, via either pharmacological (NNMT inhibitors) or genetic approach (siRNA transfection), provided protection against palmitate lipotoxicity. Our further mechanistic exploration identified protein kinase A (PKA) activation to contribute, at least, partially to the protective effect of NNMT inhibition against lipotoxicity. Collectively, our data demonstrated that NNMT upregulation by the mTORC1-ATF4 pathway activation contributes to the development of lipotoxicity in hepatocytes.

scholarly journals The Scleraxis Transcription Factor Directly Regulates Multiple Distinct Molecular and Cellular Processes During Early Tendon Cell Differentiation

2021 ◽  
Vol 9 ◽  
Author(s):  
Han Liu ◽  
Jingyue Xu ◽  
Yu Lan ◽  
Hee-Woong Lim ◽  
Rulang Jiang
Keyword(s):  
Transcription Factor ◽  
Cell Differentiation ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Rna Seq ◽  
Tendon Cell ◽  
Tendon Development ◽  
Genome Wide ◽  
Direct Target ◽  
Embryonic Tendon

Proper development of tendons is crucial for the integration and function of the musculoskeletal system. Currently little is known about the molecular mechanisms controlling tendon development and tendon cell differentiation. The transcription factor Scleraxis (Scx) is expressed throughout tendon development and plays essential roles in both embryonic tendon development and adult tendon healing, but few direct target genes of Scx in tendon development have been reported and genome-wide identification of Scx direct target genes in vivo has been lacking. In this study, we have generated a ScxFlag knockin mouse strain, which produces fully functional endogenous Scx proteins containing a 2xFLAG epitope tag at the carboxy terminus. We mapped the genome-wide Scx binding sites in the developing limb tendon tissues, identifying 12,097 high quality Scx regulatory cis-elements in-around 7,520 genes. Comparative analysis with previously reported embryonic tendon cell RNA-seq data identified 490 candidate Scx direct target genes in early tendon development. Furthermore, we characterized a new Scx gene-knockout mouse line and performed whole transcriptome RNA sequencing analysis of E15.5 forelimb tendon cells from Scx–/– embryos and control littermates, identifying 68 genes whose expression in the developing tendon tissues significantly depended on Scx function. Combined analysis of the ChIP-seq and RNA-seq data yielded 32 direct target genes that required Scx for activation and an additional 17 target genes whose expression was suppressed by Scx during early tendon development. We further analyzed and validated Scx-dependent tendon-specific expression patterns of a subset of the target genes, including Fmod, Kera, Htra3, Ssc5d, Tnmd, and Zfp185, by in situ hybridization and real-time quantitative polymerase chain reaction assays. These results provide novel insights into the molecular mechanisms mediating Scx function in tendon development and homeostasis. The ChIP-seq and RNA-seq data provide a rich resource for aiding design of further studies of the mechanisms regulating tendon cell differentiation and tendon tissue regeneration. The ScxFlag mice provide a valuable new tool for unraveling the molecular mechanisms involving Scx in the protein interaction and gene-regulatory networks underlying many developmental and disease processes.

scholarly journals Biological Activity of Lenalidomide and Its Underlying Therapeutic Effects in Multiple Myeloma

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Roberta Martiniani ◽  
Valentina Di Loreto ◽  
Chiara Di Sano ◽  
Alessandra Lombardo ◽  
Anna Marina Liberati
Keyword(s):  
Multiple Myeloma ◽  
Chemical Structure ◽  
Molecular Mechanisms ◽  
Hematologic Malignancies ◽  
Review Article ◽  
Therapeutic Effects ◽  
Immunomodulatory Drugs ◽  
Antitumor Effects ◽  
Synthetic Compound ◽  
Pleiotropic Properties

Lenalidomide is a synthetic compound derived by modifying the chemical structure of thalidomide. It belongs to the second generation of immunomodulatory drugs (IMiDs) and possesses pleiotropic properties. Even if lenalidomide has been shown to be active in the treatment of several hematologic malignancies, this review article is mostly focalized on its mode of action in multiple myeloma. The present paper is about the direct and indirect antitumor effects of lenalidomide on malignant plasmacells, bone marrow microenvironment, bone resorption and host’s immune response. The molecular mechanisms and targets of lenalidomide remain largely unknown, but recent evidence shows cereblon (CRBN) as a possible mediator of its therapeutical effects.

scholarly journals Identification of a PGXPP degron motif in dishevelled and structural basis for its binding to the E3 ligase KLHL12

2020 ◽  
Author(s):  
Zhuoyao Chen ◽  
Gregory A. Wasney ◽  
Sarah Picaud ◽  
Panagis Filippakopoulos ◽  
Masoud Vedadi ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Hydrophobic Interactions ◽  
E3 Ligase ◽  
Structural Basis ◽  
Binding Mechanism ◽  
Ring E3 Ligase ◽  
Family Protein ◽  
Kelch Domain ◽  
Ring E3 ◽  
New Protein

ABSTRACTWnt signaling is critically dependent on dishevelled proteins (DVL1-3), which are required to assemble an intracellular Wnt signalosome at the plasma membrane. The levels of dishevelled proteins are strictly regulated by multiple E3 ubiquitin ligases that target DVL1-3 for ubiquitination and proteasomal degradation. The BTB-Kelch family protein KLHL12 is a substrate-specific adaptor for a Cullin-RING E3 ligase complex that contains Cullin3 and Rbx1. KLHL12 was the first E3 ligase to be identified for DVL1-3, but the molecular mechanisms determining its substrate interactions have remained unknown. Here, we mapped the interaction of DVL1-3 to a ‘PGXPP’ motif that is conserved in other known partners and substrates of KLHL12, including PLEXHA4, PEF1 and SEC31. A 20-mer peptide containing the DVL1 motif bound to the Kelch domain of KLHL12 with low micromolar affinity. In cells, the mutation or deletion of this motif caused a striking reduction in the binding, ubiquitination and stability of DVL1 confirming this sequence as a degron motif for KLHL12 recruitment. To determine the binding mechanism we solved a 2.4 Å crystal structure of the Kelch domain of KLHL12 in complex with a DVL1 peptide. The structure revealed that the DVL1 substrate adopted a U-shaped turn conformation that enabled hydrophobic interactions with all six blades of the Kelch domain β-propeller. Overall, these results define the molecular mechanisms determining DVL regulation by KLHL12 and establish the KLHL12 Kelch domain as a new protein interaction module for a novel proline-rich motif.

scholarly journals Ubiquitylation activates a peptidase that promotes cleavage and destabilization of its activating E3 ligases and diverse growth regulatory proteins to limit cell proliferation in Arabidopsis

2016 ◽  
Author(s):  
Hui Dong ◽  
Jack Dumenil ◽  
Fu-Hao Lu ◽  
Li Na ◽  
Hannes Vanhaeren ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Molecular Mechanisms ◽  
Regulatory Proteins ◽  
Peptidase Activity ◽  
Organ Growth ◽  
E3 Ligases ◽  
Promote Cell Proliferation ◽  
Ring E3 Ligase ◽  
Ring E3 Ligases ◽  
Ring E3

ABSTRACTThe characteristic shapes and sizes of organs are established by cell proliferation patterns and final cell sizes, but the underlying molecular mechanisms coordinating these are poorly understood. Here we characterize a ubiquitin-activated peptidase called DA1 that limits the duration of cell proliferation during organ growth in Arabidopsis thaliana. The peptidase is activated by two RING E3 ligases, BB and DA2, which are subsequently cleaved by the activated peptidase and destabilized. In the case of BB, cleavage leads to destabilization by the RING E3 ligase PRT1 of the N-end rule pathway. DA1 peptidase activity also cleaves the de-ubiquitylase UBP15, which promotes cell proliferation, and the transcription factors TCP15 and TCP22, which promote cell proliferation proliferation and repress endoreduplication. We propose that DA1 peptidase activity regulates the duration of cell proliferation and the transition to endoreduplication and differentiation during organ formation in plants by coordinating the destabilization of regulatory proteins.

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