BCLAF1 and its splicing regulator SRSF10 regulate the tumorigenic potential of colon cancer cells

Zhou, Xuexia; Li, Xuebing; Cheng, Yuanming; Wu, Wenwu; Xie, Zhiqin; Xi, Qiulei; Han, Jun; Wu, Guohao; Fang, Jing; Feng, Ying

doi:10.1038/ncomms5581

Cited by 152 publications

(164 citation statements)

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“…Since SRSF2 is known to function as a splicing regulator, we next decided to take advantage of an RNA-Seq platform to determine the role of SRSF2 in regulating AS of endogenous liver transcripts. We had used this approach with other cells to characterize the biological significance of SRSF10 as a sequencespecific splicing regulator in vivo (18,20,21 Table S2 in the supplemental material). From a total number of 6,133 splicing events, we identified 390 AS events that changed significantly in the HKO samples (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…SRSF1, SRSF2, or SRSF10 cDNA was cloned into the pcDNA3.0-hemagglutinin (HA) vector. Cells were transfected with small interfering RNA (siRNA) oligonucleotides using Lipofectamine RNAiMAX, while plasmid transfection was performed by using Lipofectamine 2000 (Invitrogen, Carlsbad, CA) as previously described (18,19). Sequences of siRNA oligonucleotides are listed in Table S1 in the supplemental material.…”

Section: Methodsmentioning

confidence: 99%

“…RNA extraction and reverse transcription-PCR (RT-PCR), quantitative PCR (qPCR), and Western blotting were all carried out as described previously (18,20). A SYBR Premix Ex Taq kit was purchased from TaKaRa (Otsu, Shiga, Japan).…”

Section: Methodsmentioning

confidence: 99%

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Liver-Specific Deletion of SRSF2 Caused Acute Liver Failure and Early Death in Mice

Cheng

Luo

et al. 2016

Molecular and Cellular Biology

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The liver performs a variety of unique functions critical for metabolic homeostasis. Here, we show that mice lacking the splicing factor SRSF2 but not SRSF1 in hepatocytes have severe liver pathology and biochemical abnormalities. Histological analyses revealed generalized hepatitis with the presence of ballooned hepatocytes and evidence of fibrosis. Molecular analysis demonstrated that SRSF2 governs splicing of multiple genes involved in the stress-induced cell death pathway in the liver. More importantly, SRSF2 also functions as a potent transcription activator, required for efficient expression of transcription factors mainly responsible for energy homeostasis and bile acid metabolism in the liver. Consistent with the effects of SRSF2 in gene regulation, accumulation of total cholesterol and bile acids was prominently observed in the mutant liver, followed by enhanced generation of reactive oxygen species and increased endoplasmic reticulum stress, as revealed by biochemical and ultrastructural analyses. Taking these observations together, inactivation of SRSF2 in liver caused dysregulated splicing events and hepatic metabolic disorders, which trigger endoplasmic reticulum stress, oxidative stress, and finally liver failure.A lternative splicing is a major driving force for expanding proteomic diversity that allows expression of protein variants critical for cell-or tissue-specific functions from a single gene (1). Splicing regulation is primarily achieved by the association of splicing factors with specific splicing elements on the pre-mRNA that determine whether to include or exclude an alternative exon (2, 3). Alterations in splicing factors or mutations in their target sequences result in dysregulated splicing products, which have been implicated in a wide range of human diseases (4, 5).Serine/arginine-rich (SRSF, previously named SR) proteins are a class of highly conserved RNA binding proteins with well-established roles in both constitutive and alternative splicing (AS) (2, 3, 6). They consist of one or two N-terminal RNA binding domains which allow binding to specific RNA sequences, a hinge region, and a C-terminal arginine/serine-rich domain responsible for protein-protein interaction (7). Apart from splicing-related functions, SRSF proteins have also been involved in other cellular processes, including mRNA nuclear export, mRNA stability, genomic stability, and translational control (8).Although most SRSF proteins show similar preferences for purine-rich motifs, individual SRSF proteins display distinct roles in cell physiology and vertebrate development. Specifically, deletion of SRSF1 in heart affects the splicing transition of the CaMKII␦ pre-mRNA during postnatal heart remodeling, causing severe excitation-contraction (EC) coupling defects in mice (9). Tissuespecific inactivation of SRSF2 had dramatic consequences on thymus development and caused T cell maturation defects (10). These findings strongly indicate that SRSF proteins act as tissuespecific regulators that play defined and nonredundant...

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Liver-Specific Deletion of SRSF2 Caused Acute Liver Failure and Early Death in Mice

Cheng

Luo

et al. 2016

Molecular and Cellular Biology

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“…In addition, Bcl-2 family members exhibit both pro- and anti-apoptotic activities on modulating the intrinsic apoptosis pathway [39]. The balance between Bcl-2 family members is meticulously determined by cell survival or apoptosis [40]. Moreover, impaired splicing profiles of Bcl-2 family members result in differential or opposite effects in regulating cell viability [27].…”

Section: Overview Of 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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“…24 Although most of studies suggest that Bclaf1 is a tumor suppressor, a recent report indicated that Bclaf1 was oncogenic in colorectal cancers. 25 Thus, the function of Bclaf1 in carcinogenesis is controversial.…”

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confidence: 99%

Bclaf1 is an important NF-κB signaling transducer and C/EBPβ regulator in DNA damage-induced senescence

Sun

Geng

et al. 2016

Cell Death Differ

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Inducing senescence in cancer cells is an effective approach to suppress cancer growth, and it contributes significantly to the efficacy of therapeutic drugs. Previous studies indicated that transcription factors NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) and C/EBPβ (CCAAT/enhancer-binding protein-β) play a critical role in the establishment of senescence by upregulating proinflammatory cytokines, notably interleukin-6 (IL-6) and interleukin-8 (IL-8). However, it is not clear how these two factors are activated in response to senescence-inducing stimuli and subsequently regulate gene transcription. Here, we reveal Bcl-2-associated transcription factor 1 (Bclaf1) as a novel player in the therapeutic drug doxorubicin-induced senescence (TIS) in multiple cancer cells. Bclaf1 is upregulated through the ATM/Nemo/NF-κB pathway during TIS and is a direct target of p65 and c-Rel. The induction of Bclaf1 by NF-κB is essential for C/EBPβ upregulation and IL-6/IL-8 transcription during TIS. Bclaf1 can interact with the leucine zipper region of C/EBPβ and cooperate with C/EBPβ to upregulate IL-8. Furthermore, we show that Bclaf1 is required for the effectiveness of doxorubicin (Dox) treatment-induced tumor suppression in a xenograft tumor model. These finding suggest that Bclaf1 plays a crucial role in transducing the senescence-inducing signal from NF-κB to C/EBPβ during TIS, thus amplifying the signals for the establishment of senescence. Given the recent revelation that Bclaf1 is involved in tumorigenesis, our data indicate that the responsiveness of Bclaf1 to NF-κB may determine the effectiveness of therapeutic drugs.

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BCLAF1 and its splicing regulator SRSF10 regulate the tumorigenic potential of colon cancer cells

Cited by 152 publications

References 45 publications

Liver-Specific Deletion of SRSF2 Caused Acute Liver Failure and Early Death in Mice

Liver-Specific Deletion of SRSF2 Caused Acute Liver Failure and Early Death in Mice

Differential Impacts of Alternative Splicing Networks on Apoptosis

Bclaf1 is an important NF-κB signaling transducer and C/EBPβ regulator in DNA damage-induced senescence

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