Two consistently deleted regions within chromosome 1p32‐pter in human non–small cell lung cancer

Chizhikov, Victor V.; Zborovskaya, I. B.; Лактионов, К. К.; Delektorskaya, V. V.; Полоцкий, Б. Е.; Tatosyan, A. G.; Gasparian, Alexander V.

doi:10.1002/mc.1023

Cited by 10 publications

(9 citation statements)

References 20 publications

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“…Receptor-interacting serine-threonine kinase (RIPK) 3, which is part of the same family as RIPK1, which contains a death domain, has never been reported to be hypermethylated in any cancers before our report. Interestingly, the locations of HIC1, RIPK3, FABP3, and PRKCDBP were reported to lose heterozygosity in lung cancer (Konishi et al 1998;Abujiang et al 1998;Chizhikov et al 2001;Petersen et al 1997).…”

Section: Resultsmentioning

confidence: 99%

Microarray analysis of promoter methylation in lung cancers

et al. 2006

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Aberrant DNA methylation is an important event in carcinogenesis. Of the various regions of a gene that can be methylated in cancers, the promoter is the most important for the regulation of gene expression. Here, we describe a microarray analysis of DNA methylation in the promoter regions of genes using a newly developed promoter-associated methylated DNA amplification DNA chip (PMAD). For each sample, methylated Hpa II-resistant DNA fragments and Msp Icleaved (unmethylated + methylated) DNA fragments were amplified and labeled with Cy3 and Cy5 respectively, then hybridized to a microarray containing the promoters of 288 cancer-related genes. Signals from Hpa II-resistant (methylated) DNA (Cy3) were normalized to signals from Msp I-cleaved (unmethylated + methylated) DNA fragments (Cy5). Normalized signals from lung cancer cell lines were compared to signals from normal lung cells. About 10.9% of the cancer-related genes were hypermethylated in lung cancer cell lines. Notably, HIC1, IRF7, ASC, RIPK3, RASSF1A, FABP3, PRKCDBP, and PAX3 genes were hypermethylated in most lung cancer cell lines examined. The expression profiles of these genes correlated to the methylation profiles of the genes, indicating that the microarray analysis of DNA methylation in the promoter region of the genes is convenient for epigenetic study. Further analysis of primary tumors indicated that the frequency of hypermethylation was high for ASC (82%) and PAX3 (86%) in all tumor types, and high for RIPK3 in small cell carcinoma (57%). This demonstrates that our PMAD method is effective at finding epigenetic changes during cancer.

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Section: Resultsmentioning

confidence: 99%

Microarray analysis of promoter methylation in lung cancers

et al. 2006

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“…Aberrant expression of Plk3 is found in multiple tumors (5, 6). The human PLK3 gene is localized to the short arm of the chromosome 1 (1p32), a region that displays loss of heterozygosity or homozygous deletions in many types of cancer and has been proposed to harbor tumor susceptibility genes (7,8). A recent mouse genetic study showed that PLK3 Ϫ/Ϫ mice develop tumors in multiple organs at an enhanced rate (4).…”

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confidence: 99%

Regulation of PTEN Stability and Activity by Plk3

Yao

Jiang

et al. 2010

Journal of Biological Chemistry

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By studying primary isogenic murine embryonic fibroblasts (MEFs), we have shown that PLK3 null MEFs contain a reduced level of phosphatase and tensin homolog (PTEN) and increased Akt1 activation coupled with decreased GSK3␤ activation under normoxia and hypoxia. Purified recombinant Plk3, but not a kinase-defective mutant, efficiently phosphorylates PTEN in vitro. Mass spectrometry identifies threonine 366 and serine 370 as two putative residues that are phosphorylated by Plk3. Immunoblotting using a phosphospecific antibody confirms these sites as Plk3 phosphorylation sites. Moreover, treatment of MEFs with LiCl, an inhibitor of GSK3␤ and CK2, only partially suppresses the phosphorylation, suggesting Plk3 as an additional kinase that phosphorylates these sites in vivo. Plk3-targeting mutants of PTEN are expressed at a reduced level in comparison with the wild-type counterpart, which is associated with an enhanced activity of PDK1, an upstream activator of Akt1. Furthermore, the reduced level of PTEN in PLK3 null MEFs is stabilized by treatment with MG132, a proteosome inhibitor. Combined, our study identifies Plk3 as a new player in the regulation of the PI3K/PDK1/ Akt signaling axis by phosphorylation and stabilization of PTEN.Plk3, a member of the Polo-like kinase family, plays an important role in regulating cell cycle checkpoint control in response to genotoxic stresses (1, 2), as well as in cellular responses to hypoxia (3, 4). Plk3 is also strongly implicated in tumorigenesis. Aberrant expression of Plk3 is found in multiple tumors (5, 6). The human PLK3 gene is localized to the short arm of the chromosome 1 (1p32), a region that displays loss of heterozygosity or homozygous deletions in many types of cancer and has been proposed to harbor tumor susceptibility genes (7,8). A recent mouse genetic study showed that PLK3 Ϫ/Ϫ mice develop tumors in multiple organs at an enhanced rate (4). Many of the tumors developed in the PLK3 null mice are large in size and are highly vascularized (4), suggesting that this kinase may be involved in regulating the angiogenesis pathway.The PTEN 3 tumor suppressor is frequently mutated in cancer cells, and inherited PTEN mutations cause cancer-susceptibility conditions, including Cowden syndrome (9 -13). The PTEN level, as well as its activity, profoundly influences tumor susceptibility because haplo-insufficiency of PTEN results in tumor development in many organs in animal models (14, 15). Biochemically, PTEN dephosphorylates the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate to generate phosphatidylinositol 3,4-bisphosphate and, by doing so, antagonizes the PI3K/Akt signaling pathway. Therefore, the PTEN tumor suppressor is a central negative regulator of the PI3K/PDK1/Akt signaling axis that controls multiple cellular functions, including cell growth, survival, proliferation, and angiogenesis (16). PTEN is also involved in regulating hypoxic responses and HIF-1␣ stability (17, 18). Loss of PTEN function and increased activities of PI3K/Akt are associated ...

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“…Multiple regions on this chromosome arm have been implicated in SCLC and non-small-cell lung cancer (NSCLC) (Girard et al, 2000;Nomoto et al, 2000;Chizhikov et al, 2001;Ashman et al, 2002). Here, we describe the construction of a unique resource for analysing 1p.…”

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confidence: 99%

Genomic and gene expression profiling of minute alterations of chromosome arm 1p in small-cell lung carcinoma cells

et al. 2005

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Genetic alterations occurring on human chromosome arm 1p are common in many types of cancer including lung, breast, neuroblastoma, pheochromocytoma, and colorectal. The identification of tumour suppressors and oncogenes on this arm has been limited by the low resolution of current technologies for fine mapping. In order to identify genetic alterations on 1p in small-cell lung carcinoma, we developed a new resource for fine mapping segmental DNA copy number alterations. We have constructed an array of 642 ordered and fingerprint-verified bacterial artificial chromosome clones spanning the 120 megabase (Mb) 1p arm from 1p11.2 to p36.33. The 1p arm of 15 small-cell lung cancer cell lines was analysed at sub-Mb resolution using this arm-specific array. Among the genetic alterations identified, two regions of recurrent amplification emerged. They were detected in at least 45% of the samples: a 580 kb region at 1p34.2 -p34.3 and a 270 kb region at 1p11.2. We further defined the potential importance of these genomic amplifications by analysing the RNA expression of the genes in these regions with Affymetrix oligonucleotide arrays and semiquantitative reverse transcriptase -polymerase chain reaction. Our data revealed overexpression of the genes HEYL, HPCAL4, BMP8, IPT, and RLF, coinciding with genomic amplification.

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Two consistently deleted regions within chromosome 1p32‐pter in human non–small cell lung cancer

Cited by 10 publications

References 20 publications

Microarray analysis of promoter methylation in lung cancers

Microarray analysis of promoter methylation in lung cancers

Regulation of PTEN Stability and Activity by Plk3

Genomic and gene expression profiling of minute alterations of chromosome arm 1p in small-cell lung carcinoma cells

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