Early embryonic lethality of mice with disrupted transcription cofactor PIMT/NCOA6IP/Tgs1 gene

Jia, Yuzhi; Viswakarma, Navin; Crawford, Susan E.; Sarkar, Joy; Rao, M. Sambasiva; Karpus, William J.; Kanwar, Yashpal S.; Zhu, Yi; Reddy, Janardan K.

doi:10.1016/j.mod.2012.08.002

Cited by 29 publications

(39 citation statements)

References 56 publications

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“…We recently showed that PIMT is essential for normal development and that disruption of PIMT results in embryonic lethality at day 3.5 [4]. To study the liver specific functions of PIMT, using Cre-LoxP strategy, we recently created a mouse strain in which PIMT was selectively deleted in liver (PIMT ΔLiv KO mice)(Figure 8A and 8B) .…”

Section: Resultsmentioning

confidence: 99%

ERK2-Mediated Phosphorylation of Transcriptional Coactivator Binding Protein PIMT/NCoA6IP at Ser298 Augments Hepatic Gluconeogenesis

et al. 2013

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PRIP-Interacting protein with methyl transferase domain (PIMT) serves as a molecular bridge between CREB-binding protein (CBP)/ E1A binding protein p300 (Ep300) -anchored histone acetyl transferase and the Mediator complex sub-unit1 (Med1) and modulates nuclear receptor transcription. Here, we report that ERK2 phosphorylates PIMT at Ser298 and enhances its ability to activate PEPCK promoter. We observed that PIMT is recruited to PEPCK promoter and adenoviral-mediated over-expression of PIMT in rat primary hepatocytes up-regulated expression of gluconeogenic genes including PEPCK. Reporter experiments with phosphomimetic PIMT mutant (PIMTS298D) suggested that conformational change may play an important role in PIMT-dependent PEPCK promoter activity. Overexpression of PIMT and Med1 together augmented hepatic glucose output in an additive manner. Importantly, expression of gluconeogenic genes and hepatic glucose output were suppressed in isolated liver specific PIMT knockout mouse hepatocytes. Furthermore, consistent with reporter experiments, PIMTS298D but not PIMTS298A augmented hepatic glucose output via up-regulating the expression of gluconeogenic genes. Pharmacological blockade of MAPK/ERK pathway using U0126, abolished PIMT/Med1-dependent gluconeogenic program leading to reduced hepatic glucose output. Further, systemic administration of T4 hormone to rats activated ERK1/2 resulting in enhanced PIMT ser298 phosphorylation. Phosphorylation of PIMT led to its increased binding to the PEPCK promoter, increased PEPCK expression and induction of gluconeogenesis in liver. Thus, ERK2-mediated phosphorylation of PIMT at Ser298 is essential in hepatic gluconeogenesis, demonstrating an important role of PIMT in the pathogenesis of hyperglycemia.

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Section: Resultsmentioning

confidence: 99%

ERK2-Mediated Phosphorylation of Transcriptional Coactivator Binding Protein PIMT/NCoA6IP at Ser298 Augments Hepatic Gluconeogenesis

et al. 2013

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“…Drosophila TGS1 is required for adult viability in both muscle and neurons (Komonyi et al, 2005;Provart et al, 2016), and loss of TGS1 function is lethal in the pupal stage. Disruption of tgs1 in mice similarly caused early embryonic lethality (Jia et al, 2012), establishing that TGS1 proteins are essential for many higher organisms.…”

Section: Discussionmentioning

confidence: 99%

Trimethylguanosine Synthase1 (TGS1) Is Essential for Chilling Tolerance

et al. 2017

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“…Finally, miR-3188 was found to reduce cell-cycle transition and proliferation in nasopharyngeal carcinoma by targeting mTOR mRNA and regulating the PI3K/ AKT signaling pathway through FOXO1 (60). In addition, it is possible that impaired processing of specific miRNAs in certain growth conditions may contribute to the embryonic lethality of TGS1-knockout mice (61).…”

Section: Exportin-1-dependent Mirna Biogenesis Occurs During Cellularmentioning

confidence: 99%

An Exportin-1–dependent microRNA biogenesis pathway during human cell quiescence

Martínez

Hayes

Barr

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The reversible state of proliferative arrest known as "cellular quiescence" plays an important role in tissue homeostasis and stem cell biology. By analyzing the expression of miRNAs and miRNAprocessing factors during quiescence in primary human fibroblasts, we identified a group of miRNAs that are induced during quiescence despite markedly reduced expression of Exportin-5, a protein required for canonical miRNA biogenesis. The biogenesis of these quiescence-induced miRNAs is independent of Exportin-5 and depends instead on Exportin-1. Moreover, these quiescence-induced primary miRNAs (pri-miRNAs) are modified with a 2,2,7-trimethylguanosine (TMG)-cap, which is known to bind Exportin-1, and knockdown of Exportin-1 or trimethylguanosine synthase 1, responsible for (TMG)-capping, inhibits their biogenesis. Surprisingly, in quiescent cells Exportin-1-dependent pri-miR-34a is present in the cytoplasm together with a small isoform of Drosha, implying the existence of a different miRNA processing pathway in these cells. Our findings suggest that during quiescence the canonical miRNA biogenesis pathway is down-regulated and specific miRNAs are generated by an alternative pathway to regulate genes involved in cellular growth arrest.M ost metazoan cells enter a reversible cell-cycle arrest known as "cellular quiescence" when they are exposed to antimitogenic signals or an environment unfavorable for proliferation (1, 2). In mammalian cells, quiescence (also known as "G 0 arrest") is characterized by reduced DNA replication, altered metabolism, increased autophagy, and increased expression of cyclin-dependent kinase inhibitors such as p27 Kip1 (3,4). In vitro, quiescence can be induced in primary cells by serum starvation, contact inhibition, and loss of adhesion to a substrate (5). Quiescence is involved in important cellular processes, including the balance between differentiation and self-renewal in different types of stem cells, and dysregulation of quiescence could favor carcinogenesis. However, the molecular mechanisms that regulate quiescence are poorly understood (6). miRNAs are small, noncoding RNAs ∼22-nt long that regulate the expression of protein-coding genes by base-pairing with the 3′ UTR of mRNAs, repressing the translation and/or inducing the degradation of the target mRNA (7,8). In canonical miRNA biogenesis in mammalian cells, miRNAs are transcribed by RNA polymerase II to produce 7-methylguanosine (m 7 G)-capped primary miRNAs (pri-miRNAs) containing one or more bulged hairpin structures that are recognized by the nuclear microprocessor, which consists of the RNase III enzyme Drosha and the dsRNA-binding protein DGCR8 (DiGeorge syndrome critical region gene 8) (9-12). Specific cleavage of the pri-miRNA by the nuclear microprocessor generates an ∼70-nt stem-loop structure known as the "precursor miRNA" (pre-miRNA), which is recognized and transported to the cytoplasm by 10,11,13). Subsequently, pre-miRNA is cleaved by the cytoplasmic RNase III enzyme Dicer (14-17), generating a double-stranded mature mi...

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Early embryonic lethality of mice with disrupted transcription cofactor PIMT/NCOA6IP/Tgs1 gene

Cited by 29 publications

References 56 publications

ERK2-Mediated Phosphorylation of Transcriptional Coactivator Binding Protein PIMT/NCoA6IP at Ser298 Augments Hepatic Gluconeogenesis

ERK2-Mediated Phosphorylation of Transcriptional Coactivator Binding Protein PIMT/NCoA6IP at Ser298 Augments Hepatic Gluconeogenesis

Trimethylguanosine Synthase1 (TGS1) Is Essential for Chilling Tolerance

An Exportin-1–dependent microRNA biogenesis pathway during human cell quiescence

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