Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Regulation of cell survival is a key part of the pathogenesis of multiple myeloma (MM). Jun N-terminal kinase (JNK) signaling has been implicated in MM pathogenesis, but its function is unclear. To elucidate the role of JNK in MM, we evaluated the specific functions of the two major JNK proteins, JNK1 and JNK2. We show here that JNK2 is constitutively activated in a panel of MM cell lines and primary tumors. Using loss-of-function studies, we demonstrate that JNK2 is required for the survival of myeloma cells and constitutively suppresses JNK1-mediated apoptosis by affecting expression of poly(ADP-ribose) polymerase (PARP)14, a key regulator of B-cell survival. Strikingly, we found that PARP14 is highly expressed in myeloma plasma cells and associated with disease progression and poor survival. Overexpression of PARP14 completely rescued myeloma cells from apoptosis induced by JNK2 knockdown, indicating that PARP14 is critically involved in JNK2-dependent survival. Mechanistically, PARP14 was found to promote the survival of myeloma cells by binding and inhibiting JNK1. Moreover, inhibition of PARP14 enhances the sensitization of MM cells to anti-myeloma agents. Our findings reveal a novel regulatory pathway in myeloma cells through which JNK2 signals cell survival via PARP14, and identify PARP14 as a potential therapeutic target in myeloma.
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PMID:Poly(ADP-ribose) polymerase family member 14 (PARP14) is a novel effector of the JNK2-dependent pro-survival signal in multiple myeloma. 2304 69

Poly(ADP-ribose) polymerase 14 (PARP14) is a member of the PARP family of enzymes that transfer ADP-ribose from NAD+ to nucleophilic amino acids on target proteins, a process known as mono-ADP-ribosylation (MARylation). PARP14 is involved in normal immune function through the IL-4 signaling pathway and is a prosurvival factor in multiple myeloma and hepatocellular carcinoma. A mechanistic understanding of the physiological and pathophysiological roles of PARP14 has been limited by the dearth of PARP14-specific MARylation targets. Herein we engineered a PARP14 variant that uses an NAD+ analog that is orthogonal to wild-type PARPs for identifying PARP14-specific MARylation targets. Combining this chemical genetics approach with a BioID approach for proximity-dependent labeling of PARP14 interactors, we identified 114 PARP14-specific protein substrates, several of which are RNA regulatory proteins. One of these targets is PARP13, a protein known to play a role in regulating RNA stability. PARP14 MARylates PARP13 on several acidic amino acids. This study not only reveals crosstalk among PARP family members but also highlights the advantage of using disparate approaches for identifying the direct targets of individual PARP family members.
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PMID:Combining Chemical Genetics with Proximity-Dependent Labeling Reveals Cellular Targets of Poly(ADP-ribose) Polymerase 14 (PARP14). 3024 68

Poly-adenosine diphosphate-ribose polymerase (PARP) implements posttranslational mono- or poly-ADP-ribosylation modification of target proteins. Among the known 18 members in the enormous family of PARP enzymes, several investigations about PARP1, PARP2, and PARP5a/5b have been launched in the past few decades; more specifically, PARP14 is gradually emerging as a promising drug target. An intact PARP14 (also named ARTD8 or BAL2) is constructed by macro1, macro2, macro3, WWE, and the catalytic domain. PARP14 takes advantage of nicotinamide adenine dinucleotide (NAD+) as a metabolic substrate to conduct mono-ADP-ribosylation modification on target proteins, taking part in cellular responses and signaling pathways in the immune system. Therefore, PARP14 has been considered a fascinating target for treatment of tumors and allergic inflammation. More importantly, PARP14 could be a potential target for a chemosensitizer based on the theory of synthetic lethality and its unique role in homologous recombination DNA repair. This review first gives a brief introduction on several representative PARP members. Subsequently, current literatures are presented to reveal the molecular mechanisms of PARP14 as a novel drug target for cancers (e.g., diffuse large B-cell lymphoma, multiple myeloma, prostate cancer, and hepatocellular carcinoma) and allergic inflammatory. Finally, potential PARP inhibitor-associated adverse effects are discussed. The review could be a meaningful reference for innovative drug or chemosensitizer discovery targeting to PARP14.
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PMID:Research Progress on PARP14 as a Drug Target. 3089 Sep 36