Bifunctional Enzyme JMJD6 Contributes to Multiple Disease Pathogenesis: New Twist on the Old Story

Vangimalla, Shiva Shankar; Ganesan, Murali; Kharbanda, Kusum K.; Osna, Natalia A.

doi:10.3390/biom7020041

Cited by 31 publications

(26 citation statements)

References 79 publications

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“…In this study, we demonstrated Jmjd6a-mediated RNA splicing of GSK3β, which is highly a conserved kinase for cellular signaling pathways such as PI3 kinase, Wnt, Hedgehog, and Notch signaling in embryonic development, cellular differentiation, and several human diseases [56, 57]. Therefore, our findings may expand our knowledge of the functions of Jmjd6 in animal development as well as multiple human diseases including cancer [58].…”

Section: Discussionmentioning

confidence: 82%

Jmjd6a regulates GSK3β RNA splicing in Xenopus laevis eye development

et al. 2019

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It has been suggested that Jmjd6 plays an important role in gene regulation through its demethylation or hydroxylation activity on histone and transcription factors. In addition, Jmjd6 has been shown to regulate RNA splicing by interaction with splicing factors. In this study, we demonstrated that Jmjd6a is expressed in developing Xenopus laevis eye during optic vesicle formation and retinal layer differentiation stages. Knockdown of Jmjd6a by an antisense morpholino resulted in eye malformation including a deformed retinal layer and no lens formation. We further found down-regulation of gene expression related to eye development such as Rx1 , Otx2 , and Pax6 in Jmjd6a morpholino injected embryos. Jmjd6 interacts with splicing factor U2AF25 and GSK3β RNA in the anterior region of Xenopus embryos. Knockdown of Jmjd6a led to deletion of GSK3β RNA exon 1 and 2, which resulted in generation of N’-terminal truncated GSK3β protein. This event further caused decreased phosphorylation of β-catenin and subsequently increased β-catenin stability. Therefore, our result may suggest that Jmjd6a plays an important role in Xenopus eye development through regulation of GSK3β RNA splicing and canonical Wnt/β-catenin signaling.

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Section: Discussionmentioning

confidence: 82%

Jmjd6a regulates GSK3β RNA splicing in Xenopus laevis eye development

et al. 2019

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“…JMJD6 can exist in monomeric and larger oligomeric forms . Several studies showed that JMJD6 adopts an oligomeric form in solution.…”

Section: The Jmjd6 Protein and Its Structurementioning

confidence: 99%

“…One of the proposed functions of JMJD6 is catalysing arginine demethylation (Figure A). This reaction depends on the presence of cofactors, including Fe (II) and 2OG . Arginine methylation occurs in many proteins involved in various cellular functions.…”

Section: The Enzymatic Activities Of Jmjd6mentioning

confidence: 99%

Jumonji domain‐containing protein 6 protein and its role in cancer

et al. 2020

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The jumonji domain‐containing protein 6 (JMJD6) is a Fe(II)‐ and 2‐oxoglutarate (2OG)‐dependent oxygenase that catalyses lysine hydroxylation and arginine demethylation of histone and non‐histone peptides. Recently, the intrinsic tyrosine kinase activity of JMJD6 has also been reported. The JMJD6 has been implicated in embryonic development, cellular proliferation and migration, self‐tolerance induction in the thymus, and adipocyte differentiation. Not surprisingly, abnormal expression of JMJD6 may contribute to the development of many diseases, such as neuropathic pain, foot‐and‐mouth disease, gestational diabetes mellitus, hepatitis C and various types of cancer. In the present review, we summarized the structure and functions of JMJD6, with particular emphasis on the role of JMJD6 in cancer progression.

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“…JMJD6 is one of the most controversial proteins in biology 101 . It was first cloned as phosphatidylserine (PS) receptor, 102 but was corrected as a nucleus expressed protein unrelated to PS 103‐105 .…”

Section: Jmjd6 Cleaves Mepce To Release Cdk9 Complex (P‐tefb)mentioning

confidence: 99%

The potential underlying mechanism of the leukemia caused by MLL‐fusion and potential treatments

Liu

Lee

Zhang

et al. 2020

Molecular Carcinogenesis

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A majority of infant and pediatric leukemias are caused by the mixed-lineage leukemia gene (MLL) fused with a variety of candidates. Several underlying mechanisms have been proposed. One currently popular view is that truncated MLL1 fusion and its associated complex constitutively hijacks super elongation complex, including positive transcription elongation factor b, CDK9, and cyclin T1 complex and DOT1L, to enhance the expression of transcription factors that maintain or restore stemness of leukocytes, as well as prevent the differentiation of hematopoietic progenitor cells. An alternative emerging view proposes that MLL1-fusion promotes the recruitment of TATA binding protein and RNA polymerase II (Pol II) initiation complex, so as to increase the expression levels of target genes. The fundamental mechanism of both theories are gain of function for truncated MLL1 fusions, either through Pol II elongation or initiation. Our recent progress in transcription regulation of paused Pol II through JMJD5, JMJD6, and JMJD7, combined with the repressive role of H3K4me3 revealed by others, prompted us to introduce a contrarian hypothesis: the failure to shut down transcribing units by MLL-fusions triggers the transformation: loss of function of truncated MLL1 fusions coupled with the loss of conversion of H3K4me1 to H3K4me3, leading to the constitutive expression of transcription factors that are in charge of maintenance of hematopoietic progenitor cells, may trigger the transformation of normal cells into cancer cells. Following this track, a potential treatment to eliminate these fusion proteins, which may ultimately cure the disease, is proposed. K E Y W O R D S CDK9, JMJD5, JMJD6, MLL-fusion, RNA polymerase II

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Bifunctional Enzyme JMJD6 Contributes to Multiple Disease Pathogenesis: New Twist on the Old Story

Cited by 31 publications

References 79 publications

Jmjd6a regulates GSK3β RNA splicing in Xenopus laevis eye development

Jmjd6a regulates GSK3β RNA splicing in Xenopus laevis eye development

Jumonji domain‐containing protein 6 protein and its role in cancer

The potential underlying mechanism of the leukemia caused by MLL‐fusion and potential treatments

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