Amphiregulin Induces the Alternative Splicing of p73 Into Its Oncogenic Isoform ΔEx2p73 in Human Hepatocellular Tumors

Castillo, Josefa; Goñi, Saioa; Latasa, María U.; Perugorria, María J.; Calvo, Alicia; Muntané, Jordi; Bioulac‐Sage, Paulette; Balabaud, Charles; Prieto, Jesús; Avila, Matı́as A.; Berasain, Carmen

doi:10.1053/j.gastro.2009.07.065

Cited by 68 publications

(104 citation statements)

References 36 publications

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“…Because of the limited According to the significant roles played by SLU7 in the liver, regulation of its expression and availability must be tightly controlled processes. Previous studies demonstrated the nucleocytoplasmic shuttling of SLU7 protein in response to cellular stress (1, 52), and we also described how SLU7 transcription is repressed in hepatocytes by amphiregulin, a ligand of the epidermal growth factor receptor (2,24). Here, we showed that hepatic SLU7 expression could be modulated by nutritional signals, being induced upon fasting and downregulated after feeding.…”

Section: Discussionmentioning

confidence: 52%

“…SLU7 is known as a pre-mRNA splicing regulator (51). However, the physiological role of SLU7 in vivo has not been addressed, previous works being restricted to in vitro observations (24,52). Our microarray analyses demonstrated SLU7 participation in the regulation of splicing and expression of genes implicated in RNA modification and liver metabolism.…”

Section: Discussionmentioning

confidence: 79%

“…These observations highlight the importance of accurate pre-mRNA splicing for liver homeostasis and the implication of deranged splicing in disease progression (22). Recently we reported that SLU7, a splicing factor critical for the correct selection of the 3′ splice site (23), was downregulated in human cirrhotic liver and HCC and that loss of SLU7 resulted in the aberrant production of a protumorigenic splice variant of the P73 tumor suppressor (24). Here we identified SLU7 as a fundamental gene for hepatocellular differentiation and quiescence.…”

Section: Introductionmentioning

confidence: 99%

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Splicing regulator SLU7 is essential for maintaining liver homeostasis

Elizalde¹,

Urtasun²,

Azkona³

et al. 2014

J. Clin. Invest.

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128

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A precise equilibrium between cellular differentiation and proliferation is fundamental for tissue homeostasis. Maintaining this balance is particularly important for the liver, a highly differentiated organ with systemic metabolic functions that is endowed with unparalleled regenerative potential. Carcinogenesis in the liver develops as the result of hepatocellular de-differentiation and uncontrolled proliferation. Here, we identified SLU7, which encodes a pre-mRNA splicing regulator that is inhibited in hepatocarcinoma, as a pivotal gene for hepatocellular homeostasis. SLU7 knockdown in human liver cells and mouse liver resulted in profound changes in pre-mRNA splicing and gene expression, leading to impaired glucose and lipid metabolism, refractoriness to key metabolic hormones, and reversion to a fetal-like gene expression pattern. Additionally, loss of SLU7 also increased hepatocellular proliferation and induced a switch to a tumor-like glycolytic phenotype. Slu7 governed the splicing and/or expression of multiple genes essential for hepatocellular differentiation, including serine/arginine-rich splicing factor 3 (Srsf3) and hepatocyte nuclear factor 4α (Hnf4α), and was critical for cAMP-regulated gene transcription. Together, out data indicate that SLU7 is central regulator of hepatocyte identity and quiescence.

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Splicing regulator SLU7 is essential for maintaining liver homeostasis

Elizalde¹,

Urtasun²,

Azkona³

et al. 2014

J. Clin. Invest.

Self Cite

128

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“…ΔNp73 plays a dominant-negative role in inhibiting the transcriptional and other biological activities of the transcriptionally active isoforms, which are linked to cancer development [38]. Accordingly, ΔNp73 is upregulated in many human cancers including liver, ovarian, breast, and melanoma [28,29,[39][40][41]. The correlation of 53Bp1 nuclear expression pattern and TP73 does not explicitly indicate that unstable 53BP1 expression underlies the aberrant TP73 expression.…”

Section: Discussionmentioning

confidence: 99%

“…These results suggested that amplification of 1p36 might be one of the defining genomic features of oncocytic FA. These data led us to focus on the tumor protein TP73 in 1p36, which has been shown to be frequently dysregulated during carcinogenesis in various malignancies [28,29]. Representative images of TP73 expression in both oncocytic and conventional FA obtained using immunohistochemistry are depicted in Fig.…”

Section: Amplification Of Chromosome 1p36 In Oncocytic Famentioning

confidence: 99%

Association between p53-binding protein 1 expression and genomic instability in oncocytic follicular adenoma of the thyroid

et al. 2016

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Abstract. Oncocytic follicular adenomas (FAs) of the thyroid are neoplasms of follicular cell origin that are predominantly composed of large polygonal cells with eosinophilic and granular cytoplasm. However, the pathological characteristics of these tumors are largely unexplored. Both the initiation and progression of cancer can be caused by an accumulation of genetic mutations that can induce genomic instability. Thus, the aim of this study was to evaluate the extent of genomic instability in oncocytic FA. As the presence of p53-binding protein 1 (53BP1) in nuclear foci has been found to reflect DNA double-strand breaks that are triggered by various stresses, the immunofluorescence expression pattern of 53BP-1 was assessed in oncocytic and conventional FA. The association with the degree of DNA copy number aberration (CNA) was also evaluated using array-based comparative genomic hybridization. Data from this study demonstrated increased 53BP1 expression (i.e., "unstable" expression) in nuclear foci of oncocytic FA and a higher incidence of CNAs compared with conventional FA. There was also a particular focus on the amplification of chromosome 1p36 in oncocytic FA, which includes the locus for Tumor protein 73, a member of the p53 family implicated as a factor in the development of malignancies. Further evaluations revealed that unstable 53BP1 expression had a significant positive correlation with the levels of expression of Tumor protein 73. These data suggest a higher level of genomic instability in oncocytic FA compared with conventional FA, and a possible relationship between oncocytic FA and abnormal amplification of Tumor protein 73.Key words: Thyroid oncocytic tumor, 53BP1, DNA damage response, Genomic instability plasms of follicular cell origin predominantly, or entirely, composed of large polygonal cells with oxyphilic features related to the presence of eosinophilic and granular cytoplasm that is rich in mitochondria [1][2][3]. Encapsulated thyroid lesions with no evidence of capsular or vascular invasion and no nuclear features of papillary carcinoma are diagnosed as onco-

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Changing Signals to the Spliceosome

Cooper

Patel

2012

Alternative Pre‐mRNA Splicing

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Amphiregulin Induces the Alternative Splicing of p73 Into Its Oncogenic Isoform ΔEx2p73 in Human Hepatocellular Tumors

Cited by 68 publications

References 36 publications

Splicing regulator SLU7 is essential for maintaining liver homeostasis

Splicing regulator SLU7 is essential for maintaining liver homeostasis

Association between p53-binding protein 1 expression and genomic instability in oncocytic follicular adenoma of the thyroid

Changing Signals to the Spliceosome

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