Splicing Factor SLU7 Prevents Oxidative Stress‐Mediated Hepatocyte Nuclear Factor 4α Degradation, Preserving Hepatic Differentiation and Protecting From Liver Damage

Gárate-Rascón, María; Recalde, Miriam; Jimenez, Maddalen; Elizalde, María; Azkona, María; Uriarte, Iker; Latasa, María U.; Urtasun, Raquel; Bilbao, I.; Sangro, Bruno; Garcı́a-Ruiz, Carmen; Fernández-Checa, José C.; Corrales, Fernando J.; Esquivel, Argitxu; Pineda‐Lucena, Antonio; Fernández‐Barrena, Maite G.; Ávila, Matías A.; Arechederra, María; Berasain, Carmen

doi:10.1002/hep.32029

Cited by 18 publications

(35 citation statements)

References 56 publications

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“…We also demonstrated how HNF4 protein stability can be critically regulated by a novel antioxidant role of SLU7 in hepatocytes [117]. Consequently, the downregulation of SLU7 in mouse liver results in the reduced expression of P1 promoter HNF4 isoforms, and enhanced P2 promoter activity, a response exacerbated during chronic liver injury [76,117].…”

Section: Loss Of Hepatic Function In Liver Diseasementioning

confidence: 84%

“…Interestingly, in that early study we also described how TGF downregulated HNF4 levels in hepatocytes through the induction of the transcription factor Wilm's tumor 1 (WT1), a fetal gene reactivated during hepatocellular dedifferentiation in human cirrhosis [94,112]. Since then, a plethora of studies have confirmed and extended these original findings, describing the impairment of HNF4 expression and regulatory activity in human chronic liver disease of viral, alcoholic or metabolic origin [49,54,89,90,[113][114][115], as well as in acute liver failure [54,63,116,117]. Complementary studies in human tissues and experimental models also identified changes in the ratio of HNF4 P1-and J o u r n a l P r e -p r o o f P2-derived isoforms and in HNF4 subcellular localization [118].…”

Section: Loss Of Hepatic Function In Liver Diseasementioning

confidence: 91%

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Loss of liver function in chronic liver disease: An identity crisis

Berasain¹,

Arechederra²,

Argemí³

et al. 2023

Journal of Hepatology

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Section: Loss Of Hepatic Function In Liver Diseasementioning

confidence: 84%

Section: Loss Of Hepatic Function In Liver Diseasementioning

confidence: 91%

Loss of liver function in chronic liver disease: An identity crisis

Berasain¹,

Arechederra²,

Argemí³

et al. 2023

Journal of Hepatology

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“…In both human and animal models, the step II splicing regulator SLU7 has been found down-regulated in HCC, as well as in preneoplastic conditions, such as liver cirrhosis [ 66 , 67 ]. The reduced SLU7 expression has been associated with the activation of the epidermal growth factor receptor (EGFR) by its ligand amphiregulin (AREG) during inflammation [ 66 ], which has also been linked to the down-regulation of other splicing regulators, such as the SR protein SRSF3 [ 68 , 69 ].…”

Section: Liver Cancer-associated Alterations In the Spliceosome Machinerymentioning

confidence: 99%

Impact of Alternative Splicing Variants on Liver Cancer Biology

Marin

Reviejo

Soto

et al. 2021

Cancers

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The two most frequent primary cancers affecting the liver, whose incidence is growing worldwide, are hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), which are among the five most lethal solid tumors with meager 5-year survival rates. The common difficulty in most cases to reach an early diagnosis, the aggressive invasiveness of both tumors, and the lack of favorable response to pharmacotherapy, either classical chemotherapy or modern targeted therapy, account for the poor outcome of these patients. Alternative splicing (AS) during pre-mRNA maturation results in changes that might affect proteins involved in different aspects of cancer biology, such as cell cycle dysregulation, cytoskeleton disorganization, migration, and adhesion, which favors carcinogenesis, tumor promotion, and progression, allowing cancer cells to escape from pharmacological treatments. Reasons accounting for cancer-associated aberrant splicing include mutations that create or disrupt splicing sites or splicing enhancers or silencers, abnormal expression of splicing factors, and impaired signaling pathways affecting the activity of the splicing machinery. Here we have reviewed the available information regarding the impact of AS on liver carcinogenesis and the development of malignant characteristics of HCC and iCCA, whose understanding is required to develop novel therapeutical approaches aimed at manipulating the phenotype of cancer cells.

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“…Subsequent works identified its human homologue and characterized its role in the spliceosome [ 9 , 10 , 11 , 12 , 13 , 14 ], highlighting that SLU7 controls the diversity of gene transcripts in a cell. In addition, more recent findings have identified SLU7 also involved in other levels of gene expression regulation [ 15 , 16 , 17 , 18 , 19 , 20 ]. Specifically, SLU7 has been implicated in the epigenetic remodeling of DNA, in the modulation of the transcriptional activity and in controlling protein stability.…”

Section: Introductionmentioning

confidence: 99%

“…Specifically, SLU7 has been implicated in the epigenetic remodeling of DNA, in the modulation of the transcriptional activity and in controlling protein stability. All these findings identify SLU7 as a pleiotropic factor with a holistic function at different levels of gene expression regulation [ 15 , 16 , 17 , 18 , 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

SLU7: A New Hub of Gene Expression Regulation—From Epigenetics to Protein Stability in Health and Disease

Gárate-Rascón

Recalde

Rojo

et al. 2022

IJMS

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SLU7 (Splicing factor synergistic lethal with U5 snRNA 7) was first identified as a splicing factor necessary for the correct selection of 3′ splice sites, strongly impacting on the diversity of gene transcripts in a cell. More recent studies have uncovered new and non-redundant roles of SLU7 as an integrative hub of different levels of gene expression regulation, including epigenetic DNA remodeling, modulation of transcription and protein stability. Here we review those findings, the multiple factors and mechanisms implicated as well as the cellular functions affected. For instance, SLU7 is essential to secure liver differentiation, genome integrity acting at different levels and a correct cell cycle progression. Accordingly, the aberrant expression of SLU7 could be associated with human diseases including cancer, although strikingly, it is an essential survival factor for cancer cells. Finally, we discuss the implications of SLU7 in pathophysiology, with particular emphasis on the progression of liver disease and its possible role as a therapeutic target in human cancer.

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Splicing Factor SLU7 Prevents Oxidative Stress‐Mediated Hepatocyte Nuclear Factor 4α Degradation, Preserving Hepatic Differentiation and Protecting From Liver Damage

Cited by 18 publications

References 56 publications

Loss of liver function in chronic liver disease: An identity crisis

Loss of liver function in chronic liver disease: An identity crisis

Impact of Alternative Splicing Variants on Liver Cancer Biology

SLU7: A New Hub of Gene Expression Regulation—From Epigenetics to Protein Stability in Health and Disease

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