Exon 9 skipping of apoptotic caspase-2 pre-mRNA is promoted by SRSF3 through interaction with exon 8

Jang, Ha Na; Loh, Tiing Jen; Choi, Seung W.; Moon, Heegyum; Cho, Sunghee; Hong, Seong Eui; Kim, Do Han; Sheng, Zhi; Green, Michael R.; Park, Daeho; Zheng, Xuexiu; Shen, Haihong

doi:10.1016/j.bbagrm.2013.11.006

Cited by 28 publications

(37 citation statements)

References 39 publications

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“…27 Another interesting possibility is that the binding sites within exon 15 may also control the splicing of exon 16, as SRSF3 has been shown in Caspase2 mRNA to cause the skipping of an exon (exon 9) by binding to ESS in an upstream exon (exon 8). 28 Therefore SRSF3 may promote the proximal splice site selection and inhibit distal splice site selection.…”

Section: Discussionmentioning

confidence: 99%

SRSF3 and hnRNP H1 regulate a splicing hotspot of HER2 in breast cancer cells

et al. 2015

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Keywords: breast cancer, HER2, hnRNP H1, RNA binding proteins, splice variants, SRSF3Overexpression of the oncogene HER2 occurs in 20-30% of invasive breast cancer and is associated with poor prognosis. A number of different splice variants of HER2 have been identified which produce functionally different proteins. Previously these splice variants have been investigated separately, but in the present study we collectively look at the expression and regulation of a group of HER2 splice variants produced by a splicing hotspot. Initial investigation in a cohort of tumor samples showed large variations in HER2 variant expression between patient samples. RNA interference studies identified 2 splicing factors involved in the regulation of splicing within this region, hnRNP H1 and SRSF3. siRNA targeting hnRNP H1 increases levels of X5 and the oncogenic variant D16HER2. Furthermore RNA chromatography assays demonstrated binding of hnRNP H1 to RNA in this region. Additionally the proto-oncogene SRSF3 was also identified as an important regulator of splicing with SRSF3 knockdown resulting in changes in all the splice variants located at the hotspot. Most notably knockdown of SRSF3 resulted in a switch from the oncogenic D16HER2 to p100 which inhibits cell proliferation. Binding of SRSF3 to RNA within this region was also demonstrated by RNA chromatography and more specifically 2 SRSF3 binding sites were identified within exon 15. SRSF3 and hnRNP H1 are the first splicing factors identified which regulate the production of these functionally distinct HER2 splice variants and therefore maybe important for the regulation of HER2 signaling.

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Section: Discussionmentioning

confidence: 99%

SRSF3 and hnRNP H1 regulate a splicing hotspot of HER2 in breast cancer cells

et al. 2015

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“…SRSF3 reportedly modulated the alternative splicing of several apoptosis-related genes, such as caspase-2 ( Casp2 ), programmed cell death 4 ( PDCD4 ), and homeodomain-interacting protein kinase-2 ( HIPK2 ) in distinct cancer cells [109,110,111]. Caspase-2 was demonstrated to act the early initiator in the intrinsic apoptosis pathway [112].…”

Section: Impacts Of Alternative Splicing Events On Apoptosismentioning

confidence: 99%

Differential Impacts of Alternative Splicing Networks on Apoptosis

Lin

Tsao

Lin

2016

IJMS

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Apoptosis functions as a common mechanism to eliminate unnecessary or damaged cells during cell renewal and tissue development in multicellular organisms. More than 200 proteins constitute complex networks involved in apoptotic regulation. Imbalanced expressions of apoptosis-related factors frequently lead to malignant diseases. The biological functions of several apoptotic factors are manipulated through alternative splicing mechanisms which expand gene diversity by generating discrete variants from one messenger RNA precursor. It is widely observed that alternatively-spliced variants encoded from apoptosis-related genes exhibit differential effects on apoptotic regulation. Alternative splicing events are meticulously regulated by the interplay between trans-splicing factors and cis-responsive elements surrounding the regulated exons. The major focus of this review is to highlight recent studies that illustrate the influences of alternative splicing networks on apoptotic regulation which participates in diverse cellular processes and diseases.

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“…Intriguingly, the sequencing of this band confirmed an exon 5 skipping. This event could be consistent with the inactivation of the ESEs placed on the adjacent exon . It is suggested that the SRSF2 protein would be regulating exon 5 inclusion through its interaction with the ESEs placed on exon 6.…”

Section: Discussionmentioning

confidence: 58%

Unraveling the molecular effect of a rare missense mutation in BRIP1 associated with inherited breast cancer

Velázquez

Esteban-Cardeñosa

Lastra³

et al. 2018

Molecular Carcinogenesis

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BRIP1 is a component of the Fanconi Anemia/BRCA pathway responsible for DNA reparation via helicase activity. Some heterozygous variants in BRIP1 could contribute to Hereditary Breast Cancer through a defective DNA repair. The clinical utility of BRIP1 mutations in a familial cancer context is compromised by the conflicting interpretation of "variants of uncertain significance" (VUS). Defining the clinical significance of variants identified in genetic tests is a major challenge; therefore, studies that evaluate the biological effect of these variants are definitely necessary. To contribute to this purpose, we have characterized the variant c.550G>T of BRIP1, a missense mutation with little evidence about its pathogenicity. Since Human Splicing Finder predicts the creation of a new exonic splicing enhancer site we decided to perform cDNA analysis revealing that the c.550G>T mutation located in exon 6 led to an aberrant transcript causing exon 5 skipping. Our results demonstrate that the c.550G>T BRIP1 variant disrupts normal splicing, causing exon 5 skipping. Considering that the exon 5 encodes the helicase domain of BRIP1, it is expected an alteration of the function. This finding enhances the interpretation of this VUS, suggesting a potential pathogenic effect.

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Exon 9 skipping of apoptotic caspase-2 pre-mRNA is promoted by SRSF3 through interaction with exon 8

Cited by 28 publications

References 39 publications

SRSF3 and hnRNP H1 regulate a splicing hotspot of HER2 in breast cancer cells

SRSF3 and hnRNP H1 regulate a splicing hotspot of HER2 in breast cancer cells

Differential Impacts of Alternative Splicing Networks on Apoptosis

Unraveling the molecular effect of a rare missense mutation in BRIP1 associated with inherited breast cancer

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