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Mammalian CYP2D Members A Comparison of Structure, Function, and Regulation
Published in Shufeng Zhou, Cytochrome P450 2D6, 2018
The rat Cyp2d2 gene is positively regulated by the poly(C)-binding protein heterogeneous nuclear ribonucleoprotein K (hnRNP K) through a transcriptional regulatory element located in the 5’-flanking region from −94 to −113 (Sakai et al. 2009). A single substitution within the transcriptional regulatory element of the Cyp2d2 gene is found in DA rats. The mutation is detected in the polypyrimidine sequence, which is the preferred binding site for the hnRNP K protein. The mutation within the transcriptional regulatory element attenuates the binding of the hnRNP K protein. It appears that decreased recruitment of the hnRNP K protein to the mutated sequence results in a low expression of Cyp2d2 mRNA in DA rats.
Blastic Transformation of Chronic Myelogenous Leukemia: Does BCR-ABL Orchestrate Disease Progression?
Published in Jorge Cortes, Michael Deininger, Chronic Myeloid Leukemia, 2006
Calabretta Bruno, Perrotti Danilo
In BCR-ABL-expressing myeloid and lymphoid progenitor cells and in CML-BCCD34+ but not CML-CPCD34+ patient cells, BCR-ABL kinase activity induces HNRPK expression by enhancing Hnrpk gene transcription and mRNA stability through a mechanism that depends on the BCR-ABL-regulated activity of MAPKERK1/2 (39). In fact, BCR-ABL graded expression activates MAPKERK1/2 and increases HNRPK levels in a dose-dependent manner. Knockdown of the RNA binding protein HNRPK inhibits growth factor-independent proliferation, colony formation, and tumorigenesis of BCR-ABL-expressing myeloid progenitors (39). Interestingly, HNRPK downregulation reduces levels of Myc (39), which is transcriptionally and translationally induced by HNRPK (52,53). In BCR-ABL-transformed cells, HNRPK translation-regulatory activity, which depends on phosphorylation of HNRPK on serines 284 and 353 by the BCR-ABL-activated MAPKERK1/2, is necessary for cytokine-independent proliferation, colony formation, and in vivo BCR-ABL leukemogenic potential of the 32D-BCR-ABL cell line and/or of primary CD34+ CML-BC (39). The requirement of HNRPK for BCR-ABL leukemogenesis depends in part on its ability to bind the IRES element of MYC mRNA and enhance MYC mRNA translation (39). In fact, restoration of MYC expression is sufficient to rescue factor-independent colony formation and leukemogenic potential of 32D-BCR-ABL and primary CD34+ CML-BC cells from the inhibitory effects of dominant-negative S284/353A HNRPK (39). Consistent with the existence of a BCR-ABL-MAPK-HNRPK network positively regulating MYC mRNA translation in the advanced phase of CML, MYC protein but not mRNA expression is higher in the CD34+ fraction of CML-BC and -AP marrow cells than in the CD34+ fraction of normal and CML-CP patient marrow cells (39). Thus, one of the molecular mechanisms whereby BCR-ABL enhances MYC expression involves the MAPK-dependent regulation of HNRPK translation regulatory activity. However, increased MYC mRNA levels can be still found in CML-BC patients with amplification of the MYC gene (54,55), and transcriptional, translational, and post-translational mechanisms like those involving the activity of Jak2 kinase (48) may all participate in the regulation of MYC expression in primary CML blast crisis cells.
Long Noncoding RNA LINC00941 Promotes Cell Proliferation and Invasion by Interacting with hnRNPK in Oral Squamous Cell Carcinoma
Published in Nutrition and Cancer, 2022
Jie Liu, Zhenxing Li, Ting Zhang, Chunhui Wang, Wen Chen, Danfeng Zhang, Junyu Wang
In our study, RNA pull down assays indicated a direct interaction between LINC00941 and hnRNPK. It is known that hnRNPK expression is at steady state between the nucleus and cytoplasm and it is unclear yet how this balance is affected in the context of OSCC (45). Further investigation into the interactions between LINC00941 and hnRNPK is necessary to evaluate if this interaction is cytoplasmic, nuclear, or in exosomal compartments, as reported for lncRNA 91H in colorectal cancer (30). Investigating changes in gene expression profiles following regulation of hnRNPK will also provide critical insight into the altered expression of tumor-associated genes. In summary, this study validated a key interaction between lncRNA LINC00941 and hnRNPK that promoted cell proliferation and migration In Vitro and led to the activation of the Wnt/β-catenin signaling pathway, and EMT in OSCC cells to promote metastasis.