Localized inhibition of protein phosphatase 1 by NUAK1 promotes spliceosome activity and reveals a MYC-sensitive feedback control of transcription

Cossa, Giacomo; Roeschert, Isabelle; Prinz, Florian; Baluapuri, Apoorva; Vidal, Raphael Silveira; Schülein-Völk, Christina; Chang, Yun Chien; Ade, Carsten P.; Mastrobuoni, Guido; Girard, Cyrille; Kumar, Amit; Wortmann, Lars; Walz, Susanne; Lührmann, Reinhard; Kempa, Stefan; Küster, Bernhard; Wolf, Elmar; Mumberg, Dominik; Eilers, Martin

doi:10.1016/j.molcel.2021.05.013

Cited by 6 publications

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“…In a yeast strain with a BS mutation, Pol II accumulates over introns (Chathoth et al, 2014). Inhibition of the splicingassociated NUAK1 kinase increases Pol II occupancy near the TSS and at the first exon-intron border (Cossa et al, 2020). The U1 snRNP protects pre-mRNAs from premature cleavage and polyadenylation (Kaida et al, 2010), hence determining mRNA length (Berg et al, 2012;Oh et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Efficient RNA polymerase II pause release requires U2 snRNP function

et al. 2021

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Section: Introductionmentioning

confidence: 99%

Efficient RNA polymerase II pause release requires U2 snRNP function

et al. 2021

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“…NUAK family kinase 1 (NUAK1) was reported to play a role in oncogenesis by the improvement of glycolysis ( 40 ), induction of ferroptosis ( 41 ), and phosphorylation of downstream molecules ( 42 ). However, NUAK could prevent tumorigenesis progression due to its protective function from oxidative stress in colorectal tumors ( 43 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of senescence-related subtypes, establishment of a prognosis model, and characterization of a tumor microenvironment infiltration in breast cancer

et al. 2022

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Breast cancer is a malignancy with the highest incidence and mortality in women worldwide. Senescence is a model of arrest in the cell cycle, which plays an important role in tumor progression, while the prognostic value of cellular senescence-related genes (SRGs) in evaluating immune infiltration and clinical outcomes of breast cancer needs further investigation. In the present study, we identified two distinct molecular subtypes according to the expression profiles of 278 SRGs. We further explored the dysregulated pathways between the two subtypes and constructed a microenvironmental landscape of breast cancer. Subsequently, we established a senescence-related scoring signature based on the expression of four SRGs in the training set (GSE21653) and validated its accuracy in two validation sets (GSE20685 and GSE25055). In the training set, patients in the high-risk group had a worse prognosis than patients in the low-risk group. Multivariate Cox regression analysis showed that risk score was an independent prognostic indicator. Receiver operating characteristic curve (ROC) analysis proved the predictive accuracy of the signature. The prognostic value of this signature was further confirmed in the validation sets. We also observed that a lower risk score was associated with a higher pathological response rate in patients with neoadjuvant chemotherapy. We next performed functional experiments to validate the results above. Our study demonstrated that these cellular senescence patterns effectively grouped patients at low or high risk of disease recurrence and revealed their potential roles in the tumor–immune–stromal microenvironment. These findings enhanced our understanding of the tumor immune microenvironment and provided new insights for improving the prognosis of breast cancer patients.

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“…An overview of the functions of the kinases within this family can be found in these two reviews (Bright et al, 2009;Monteverde et al, 2015). One of the kinases most closely related to AMPK is NUAK1, which has a diverse set of functions including regulation of centrosome number, MYC-dependent splicing control, HIPPO signalling control, and importantly cellular ROS responses (Humbert et al, 2010;Port et al, 2018;Cossa et al, 2021;Whyte et al, 2023). The phosphorylation of MYPT at S445 by NUAK1 increases the activity of GSK3β for NRF2 and suppresses the cellular ROS response thereby reducing the capacity of cancer cells to maintain adaptation to high ROS production (Port et al, 2018).…”

Section: Frontiers In Molecular Biosciencesmentioning

confidence: 99%

Kinase signalling adaptation supports dysfunctional mitochondria in disease

Skalka,

Tsakovska,

Murphy

2024

Front. Mol. Biosci.

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Mitochondria form a critical control nexus which are essential for maintaining correct tissue homeostasis. An increasing number of studies have identified dysregulation of mitochondria as a driver in cancer. However, which pathways support and promote this adapted mitochondrial function? A key hallmark of cancer is perturbation of kinase signalling pathways. These pathways include mitogen activated protein kinases (MAPK), lipid secondary messenger networks, cyclic-AMP-activated (cAMP)/AMP-activated kinases (AMPK), and Ca2+/calmodulin-dependent protein kinase (CaMK) networks. These signalling pathways have multiple substrates which support initiation and persistence of cancer. Many of these are involved in the regulation of mitochondrial morphology, mitochondrial apoptosis, mitochondrial calcium homeostasis, mitochondrial associated membranes (MAMs), and retrograde ROS signalling. This review will aim to both explore how kinase signalling integrates with these critical mitochondrial pathways and highlight how these systems can be usurped to support the development of disease. In addition, we will identify areas which require further investigation to fully understand the complexities of these regulatory interactions. Overall, this review will emphasize how studying the interaction between kinase signalling and mitochondria improves our understanding of mitochondrial homeostasis and can yield novel therapeutic targets to treat disease.

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Localized inhibition of protein phosphatase 1 by NUAK1 promotes spliceosome activity and reveals a MYC-sensitive feedback control of transcription

Cited by 6 publications

References 0 publications

Efficient RNA polymerase II pause release requires U2 snRNP function

Efficient RNA polymerase II pause release requires U2 snRNP function

Identification of senescence-related subtypes, establishment of a prognosis model, and characterization of a tumor microenvironment infiltration in breast cancer

Kinase signalling adaptation supports dysfunctional mitochondria in disease

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