Journal of Genetics and Genomics

The PI3K/AKT Pathway and Renal Cell Carcinoma

Huifang Guo, Peter German, Shanshan Bai, Sean Barnes, Wei Guo, Xiangjie Qi, Hongxiang Lou, Jiyong Liang, Eric Jonasch, Gordon B. Mills, Zhiyong Ding

2015, 42(7): 343-353. doi: 10.1016/j.jgg.2015.03.003

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Abstract:
The phosphatidylinositol 3 kinase (PI3K)/AKT pathway is genetically targeted in more pathway components and in more tumor types than any other growth factor signaling pathway, and thus is frequently activated as a cancer driver. More importantly, the PI3K/AKT pathway is composed of multiple bifurcating and converging kinase cascades, providing many potential targets for cancer therapy. Renal cell carcinoma (RCC) is a high-risk and high-mortality cancer that is notoriously resistant to traditional chemotherapies or radiotherapies. The PI3K/AKT pathway is modestly mutated but highly activated in RCC, representing a promising drug target. Indeed, PI3K pathway inhibitors of the rapalog family are approved for use in RCC. Recent large-scale integrated analyses of a large number of patients have provided a molecular basis for RCC, reiterating the critical role of the PI3K/AKT pathway in this cancer. In this review, we summarize the genetic alterations of the PI3K/AKT pathway in RCC as indicated in the latest large-scale genome sequencing data, as well as treatments for RCC that target the aberrant activated PI3K/AKT pathway.

Identification of Global DNA Methylation Signatures in Glioblastoma-Derived Cancer Stem Cells

Eun-Joon Lee, Prakash Rath, Jimei Liu, Dungsung Ryu, Lirong Pei, Satish K. Noonepalle, Austin Y. Shull, Qi Feng, N. Scott Litofsky, Douglas C. Miller, Douglas C. Anthony, Mark D. Kirk, John Laterra, Libin Deng, Hong-Bo Xin, Xinguo Wang, Jeong-Hyeon Choi, Huidong Shi

2015, 42(7): 355-371. doi: 10.1016/j.jgg.2015.06.003

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Abstract:
Glioblastoma (GBM) is the most common and most aggressive primary brain tumor in adults. The existence of a small population of stem-like tumor cells that efficiently propagate tumors and resist cytotoxic therapy is one proposed mechanism leading to the resilient behavior of tumor cells and poor prognosis. In this study, we performed an in-depth analysis of the DNA methylation landscape in GBM-derived cancer stem cells (GSCs). Parallel comparisons of primary tumors and GSC lines derived from these tumors with normal controls (a neural stem cell (NSC) line and normal brain tissue) identified groups of hyper- and hypomethylated genes that display a trend of either increasing or decreasing methylation levels in the order of controls, primary GBMs, and their counterpart GSC lines, respectively. Interestingly, concurrent promoter hypermethylation and gene body hypomethylation were observed in a subset of genes including MGMT, AJAP1 and PTPRN2. These unique DNA methylation signatures were also found in primary GBM-derived xenograft tumors indicating that they are not tissue culture-related epigenetic changes. Integration of GSC-specific epigenetic signatures with gene expression analysis further identified candidate tumor suppressor genes that are frequently down-regulated in GBMs such asSPINT2, NEFM and PENK. Forced re-expression of SPINT2 reduced glioma cell proliferative capacity, anchorage independent growth, cell motility, and tumor sphere formation in vitro. The results from this study demonstrate that GSCs possess unique epigenetic signatures that may play important roles in the pathogenesis of GBM.

Additive Effect of Zfhx3/Atbf1 and Pten Deletion on Mouse Prostatic Tumorigenesis

Xiaodong Sun, Changsheng Xing, Xiaoying Fu, Jie Li, Baotong Zhang, Henry F. Frierson, Jin-Tang Dong

2015, 42(7): 373-382. doi: 10.1016/j.jgg.2015.06.004

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Abstract:
The phosphatase and tensin homolog (PTEN) and the zinc finger homeobox 3 (ZFHX3)/AT-motif binding factor 1 (ATBF1) genes have been established as tumor suppressor genes in prostate cancer by their frequent deletions and mutations in human prostate cancer and by the formation of mouse prostatic intraepithelial neoplasia (mPIN) or tumor by their deletions in mouse prostates. However, whether ZFHX3/ATBF1 deletion together with PTEN deletion facilitates prostatic tumorigenesis is unknown. In this study, we simultaneously deleted both genes in mouse prostatic epithelia and performed histological and molecular analyses. While deletion of one Pten allele alone caused low-grade (LG) mPIN as previously reported, concurrent deletion of Zfhx3/Atbf1 promoted the progression to high-grade (HG) mPIN or early carcinoma. Zfhx3/Atbf1 and Pten deletions together increased cell proliferation, disrupted the smooth muscle layer between epithelium and stroma, and increased the number of apoptotic cells. Deletion of both genes also accelerated the activation of Akt and Erk1/2 oncoproteins. These results suggest an additive effect of ZFHX3/ATBF1 and PTEN deletions on the development and progression of prostate neoplasia.

TCP1 Modulates DWF4 Expression via Directly Interacting with the GGNCCC Motifs in the Promoter Region of DWF4 in Arabidopsis thaliana

Yahu Gao, Dongzhi Zhang, Jia Li

2015, 42(7): 383-392. doi: 10.1016/j.jgg.2015.04.009

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Abstract:
Our previous studies indicated that TCP1 is a positive regulator of the brassinosteroid (BR) biosynthesis pathway by mediating the transcription of DWF4, one of the key BR biosynthetic genes in Arabidopsis thaliana. Whether TCP1 can directly bind to the promoter region of DWF4, however, has not been experimentally demonstrated. Here we provide our biochemical and genetic evidence that TCP1 mediates the expression of DWF4 by directly associating with the two GGNCCC motifs in the promoter region of DWF4. The expression levels of DWF4 are positively correlated to TCP1 abundance in planta. Electrophoretic mobility shift assays (EMSAs) using various synthetic DNA fragments suggest that the GGNCCC core sequence is critical for TCP1 binding. DNA sequences flanking the GGNCCC motifs are less important for the association of TCP1. Using DWF4p-GUS transgenic plants as an assay system, it is clearly indicated that these motifs are required for the positive regulation of DWF4 transcription by TCP1. More significantly, whole genome microarray analyses indicate that TCP1 can directly or indirectly regulate the expression of many other genes known to be important for normal plant growth and development.

Identification and Characterization of ABA-Responsive MicroRNAs in Rice

Caijuan Tian, Zhangli Zuo, Jin-Long Qiu

2015, 42(7): 393-402. doi: 10.1016/j.jgg.2015.04.008

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Abstract:
MicroRNAs (miRNAs) are endogenous non-coding small RNAs that silence genes through mRNA degradation or translational inhibition. The phytohormone abscisic acid (ABA) is essential for plant development and adaptation to abiotic and biotic stresses. In Arabidopsis, miRNAs are implicated in ABA functions. However, ABA-responsive miRNAs have not been systematically studied in rice. Here high throughput sequencing of small RNAs revealed that 107 miRNAs were differentially expressed in the rice ABA deficient mutant, Osaba1. Of these, 13 were confirmed by stem-loop RT-PCR. Among them, miR1425-5P, miR169a, miR169n, miR390-5P, miR397a and miR397b were up-regulated, but miR162b reduced in expression in Osaba1. The targets of these 13 miRNAs were predicted and validated by gene expression profiling. Interestingly, the expression levels of these miRNAs and their targets were regulated by ABA. Cleavage sites were detected on 7 of the miRNA targets by 5′-Rapid Amplification of cDNA Ends (5′-RACE). Finally, miR162b and its target OsTRE1 were shown to affect rice resistance to drought stress, suggesting that miR162b increases resistance to drought by targetingOsTRE1. Our work provides important information for further characterization and functional analysis of ABA-responsive miRNAs in rice.

Convergence of Y Chromosome STR Haplotypes from Different SNP Haplogroups Compromises Accuracy of Haplogroup Prediction

Chuan-Chao Wang, Ling-Xiang Wang, Rukesh Shrestha, Shaoqing Wen, Manfei Zhang, Xinzhu Tong, Li Jin, Hui Li

2015, 42(7): 403-407. doi: 10.1016/j.jgg.2015.03.008

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Abstract:

Behavioral Switch of Food Preference upon Sugar Deficiency Is Regulated by GPCRs in Drosophila

Chang Liu, Xiaobing Bai, Jinghan Sun, Xiaofan Zhang, Yan Li

2015, 42(7): 409-412. doi: 10.1016/j.jgg.2015.05.004

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Abstract:

2015 Vol. 42, No. 7