Association between polymorphisms in AXIN1 gene and atrial septal defect

Abstract

Context: AXIN1 is a central component of Wnt signalling pathway which is essential for embryonic development.

Objective: To investigate whether polymorphisms of AXIN1 contribute to ASD susceptibility.

Materials and methods: Three tag SNPs (rs12921862, rs370681 and rs1805105) in AXIN1 were genotyped in 208 ASD patients and 302 healthy controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in a Chinese population.

Results: Significantly increased ASD risk was observed to be associated with the A allele of rs12921862 (p?<?0.0001, OR?=?3.096, 95% CI?=?2.037–4.717). Increased ASD risk was observed to be associated with rs370681 in a codominant (p?=?0.043, OR?=?1.52, 95% CI?=?1.04–2.22) and overdominant model (p?=?0.016, OR?=?1.57, 95% CI?=?1.08–2.27).

Conclusion: rs12921862 and rs370681 may contribute to ASD susceptibility.     

Switch of FANCL,a key FA-BRCA component,between tumor suppressor and promoter by alternative splicing

Comment on: Panneerselvam J, et al. Cell Cycle 2012; 11:2947-55.     

Enhancer-Mediated Oncogenic Function of the Menin Tumor Suppressor in Breast Cancer

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癌基因和抑癌基因研究进展

癌基因和抑癌基因的发现和研究是肿瘤研究史上的一个里程碑,标志着肿瘤研究进入了分子时代,从而在更深层次上为阐明基因的结构、表达、调控、功能的改变与肿瘤形成的关系提供了科学依据和可能性,具有重要的理论和实际意义。本文概述了癌基因和抑癌基因的最新研究进展。     

染色质结构与mRNA可变剪接

mRNA的可变剪接(alternative splicing)是一种由一个mRNA前体(pre-mRNA)通过不同的剪接方式产生多个mRNA变异体(variants)的RNA加工过程。在过去很长一段时间里,人们认为mRNA剪接过程是独立于转录过程的一个转录后RNA加工过程。然而,越来越多的实验证明mRNA剪接在很大程度上是与转录偶联发生的。因此,剪接调控会受到与转录相关因素的调控。本文将对染色质与mRNA剪接调控的相关性和染色质结构调控可变剪接的分子机制进行阐述。     

Stress-resistant Translation of Cathepsin L mRNA in Breast Cancer Progression

The cysteine protease cathepsin L (CTSL) is often thought to act as a tumor promoter by enhancing tumor progression and metastasis. This goes along with increased CTSL activity in various tumor entities; however, the mechanisms leading to high CTSL levels are incompletely understood. With the help of the polyoma middle T oncogene driven breast cancer mouse model expressing a human CTSL genomic transgene, we show that CTSL indeed promotes breast cancer metastasis to the lung. During tumor formation and progression high expression levels of CTSL are maintained by enduring translation of CTSL mRNA. Interestingly, human breast cancer specimens expressed the same pattern of 5′ untranslated region (UTR) splice variants as the transgenic mice and the human cancer cell line MDA-MB 321. By polyribosome profiling of tumor tissues and human breast cancer cells, we observe an intrinsic resistance of CTSL to stress-induced shutdown of translation. This ability can be attributed to all 5′ UTR variants of CTSL and is not dependent on a previously described internal ribosomal entry site motif. In conclusion, we provide in vivo functional evidence for overexpressed CTSL as a promoter of lung metastasis, whereas high CTSL levels are maintained during tumor progression due to stress-resistant mRNA translation.     

CIAPIN1基因与肿瘤

细胞因子诱导的凋亡抑制因子1(cytokine induced apoptosis inhibitor1,CIAPIN1)是最新发现的一个细胞因子依赖性抗凋亡分子,并已经被证实是独立于Bcl家族、胱天蛋白酶(caspase)家族等之外的Ras信号转导通路中的另一个调节分子。CIAPIN1广泛分布于胎儿和成人的正常组织中,特别在分化型组织和活性代谢组织中具有很高的表达水平,但是在某些癌症发生时表达受到抑制。通过基因转染、RNA干扰等技术手段研究CIAPIN1与肿瘤发生、发展的关联,揭示了CIAPIN1表达水平的改变与肿瘤进展具有相关性,CIAPIN1有望成为一个新的肿瘤治疗靶分子。     

Survival or death: disequilibrating the oncogenic and tumor suppressive autophagy in cancer

Autophagy (macroautophagy) is an evolutionarily conserved lysosomal degradation process, in which a cell degrades long-lived proteins and damaged organelles. Recently, accumulating evidence has revealed the core molecular machinery of autophagy in carcinogenesis; however, the intricate relationship between autophagy and cancer continue to remain an enigma. Why does autophagy have either pro-survival (oncogenic) or pro-death (tumor suppressive) role at different cancer stages, including cancer stem cell, initiation and progression, invasion and metastasis, as well as dormancy? How does autophagy modulate a series of oncogenic and/or tumor suppressive pathways, implicated in microRNA (miRNA) involvement? Whether would targeting the oncogenic and tumor suppressive autophagic network be a novel strategy for drug discovery? To address these problems, we focus on summarizing the dynamic oncogenic and tumor suppressive roles of autophagy and their relevant small-molecule drugs, which would provide a new clue to elucidate the oncosuppressive (survival or death) autophagic network as a potential therapeutic target.     

The Alternative Splicing of Cytoplasmic Polyadenylation Element Binding Protein 2 Drives Anoikis Resistance and the Metastasis of Triple Negative Breast Cancer

Triple negative breast cancer (TNBC) represents an anomalous subset of breast cancer with a greatly reduced (30%) 5-year survival rate. The enhanced mortality and morbidity of TNBC arises from the high metastatic rate, which requires the acquisition of AnR, a process whereby anchorage-dependent cells become resistant to cell death induced by detachment. In this study TNBC cell lines were selected for AnR, and these cell lines demonstrated dramatic enhancement in the formation of lung metastases as compared with parental cells. Genetic analysis of the AnR subclones versus parental cells via next generation sequencing and analysis of global alternative RNA splicing identified that the mRNA splicing of cytoplasmic polyadenylation element binding 2 (CPEB2), a translational regulator, was altered in AnR TNBC cells. Specifically, increased inclusion of exon 4 into the mature mRNA to produce the CPEB2B isoform was observed in AnR cell lines. Molecular manipulations of CPEB2 splice variants demonstrated a key role for this RNA splicing event in the resistance of cells to anoikis. Specifically, down-regulation of the CPEB2B isoform using siRNA re-sensitized the AnR cell lines to detachment-induced cell death. The ectopic expression of CPEB2B in parental TNBC cell lines induced AnR and dramatically increased metastatic potential. Importantly, alterations in the alternative splicing of CPEB2 were also observed in human TNBC and additional subtypes of human breast cancer tumors linked to a high metastatic rate. Our findings demonstrate that the regulation of CPEB2 mRNA splicing is a key mechanism in AnR and a driving force in TNBC metastasis.     

GRWD1, a new player among oncogenesis-related ribosomal/nucleolar proteins

Increasing attention has been paid to certain ribosomal or ribosome biosynthesis-related proteins involved in oncogenesis. Members of one group are classified as “tumor suppressive factors” represented by RPL5 and RPL11; loss of their functions leads to cancer predisposition. RPL5 and RPL11 prevent tumorigenesis by binding to and inhibiting the MDM2 ubiquitin ligase and thereby up-regulating p53. Many other candidate tumor suppressive ribosomal/nucleolar proteins have been suggested. However, it remains to be experimentally clarified whether many of these factors can actually prevent tumorigenesis and if so, how they do so. Conversely, some ribosomal/nucleolar proteins promote tumorigenesis. For example, PICT1 binds to and anchors RPL11 in nucleoli, down-regulating p53 and promoting tumorigenesis. GRWD1 was recently identified as another such factor. When overexpressed, GRWD1 suppresses p53 and transforms normal human cells, probably by binding to RPL11 and sequestrating it from MDM2. However, other pathways may also be involved.