A comparison of genomic structures and expression patterns of two closely related flanking genes in a critical lung cancer region at 3p21.3

Timmer, Tineke; Terpstra, Peter; Berg, Anke van den; Pm, Veldhuis; A, Ter Elst; Voutsinas, Gerassimos E.; Mm, Hulsbeek; Draaijers, Tineke G.; Mw, Looman; K, Kok; Sl, Naylor; Buys, C. H. C. M.

doi:10.1038/sj.ejhg.5200334

Cited by 45 publications

(70 citation statements)

References 13 publications

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“…This finding, although it needs to be validated by actual experiments, such as a gel-shift assay, is in a good correlation with the previous observations that the H37 protein contains RNA-binding motifs (i.e., RBM5 is another name for H37/Luca15; refs. 15,32), and H37 shows in vitro RNA-binding activity (33). Taken together, our current hypothesis is that H37 may function in some aspects of post-transcriptional regulations of certain important proteins involved in cell cycle and/or apoptosis (i.e., Bax, cyclin A, RB, etc.).…”

Section: Discussionmentioning

confidence: 74%

3p21.3 Tumor Suppressor Gene H37/Luca15/RBM5 Inhibits Growth of Human Lung Cancer Cells through Cell Cycle Arrest and Apoptosis

Razfar

Delgado

et al. 2006

Cancer Research

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Deletion at chromosome 3p21.3 is the earliest and the most frequently observed genetic alteration in lung cancer, suggesting that the region contains tumor suppressor gene(s) (TSG). Identification of those genes may lead to the development both of biomarkers to identify high-risk individuals and novel therapeutics. Previously, we cloned the H37/Luca15/RBM5 gene from 3p21.3 and showed its TSG characteristics. To investigate the physiologic function of H37 in the lung and its mechanism of tumor suppression, we have stably transfected H37 into A549 non-small cell lung cancer cells. A549/H37 cells show significant growth inhibition compared with the vector controls by in vitro and in vivo cell proliferation assays. Using this lung cancer cell model, we have found that the molecular mechanism of H37 tumor suppression involves both cell cycle (G 1 ) arrest and apoptosis. To further define H37's function in cell cycle/apoptotic pathways, we investigated differential expression profiles of various cell cycle and apoptosis regulatory proteins using Western blot analysis. Both cyclin A and phophorylated RB levels were decreased in H37-transfected cells, whereas expression of Bax protein was increased. Mitochondrial regulation of apoptosis further downstream of Bax was investigated, showing change in the mitochondrial membrane potential, cytochrome c release into the cytosol, and enhanced caspase-9 and caspase-3 activities. We also report that H37 may mediate apoptosis in a p53-independent manner, and Bax knockdown by small interfering RNA suggests Bax plays a functional role downstream of H37. Lastly, we proposed a tumor suppression model of H37 as a post-transcriptional regulator for cell cycle/apoptotic-related proteins.

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Section: Discussionmentioning

confidence: 74%

3p21.3 Tumor Suppressor Gene H37/Luca15/RBM5 Inhibits Growth of Human Lung Cancer Cells through Cell Cycle Arrest and Apoptosis

Razfar

Delgado

et al. 2006

Cancer Research

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“…Loss of heterozygosity (LOH) occurs at 3p21.3 in 100% of small cell lung carcinoma (SCLC) cell lines, 490% of non-SCLC cell lines, and 490% of primary lung cancers (Gazdar et al, 1994), implying the existence of a lung cancer tumour suppressor gene in this region. Precise delineation of the deletions resulting in the LOH has been the focus of extensive study over the past 10 years (Daly et al, 1993;Imreh et al, 1997;Kashuba et al, 1995;Kholodnyuk et al, 1997;Kok et al, 1994;Sekido et al, 1998;Szeles et al, 1997;Todd et al, 1996;Wei et al, 1996;Yamakawa et al, 1993), and evidence exists that LUCA-15 is included in a number, but not all, of these lesions Szeles et al, 1997;Timmer et al, 1999;. However, as cancers which involve the short arm of chromosome 3 progress, the number/extent of lesions appears to increase, complicating analysis of important tumour suppressor regions (Chung et al, 1995;Kok et al, 1997).…”

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confidence: 99%

LUCA-15 suppresses CD95-mediated apoptosis in Jurkat T cells

Sutherland

Lerman²,

Williams

et al. 2001

Oncogene

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“…The RBM6 gene (1123 aa, NM_005777) spans the distal breakpoint of the NCI-H740 deletion , occupies more than 60 kb of genomic DNA, and encodes more than 16 exons expressed as a 4 kb mRNA in several human normal and lung cancer cell lines. Alternatively spliced forms have been described (Gure et al, 1998;Timmer et al, 1999). No mutations were found in 39 lung cancer cell lines.…”

Section: Rbm5 and Rbm6mentioning

confidence: 99%

“…No mutations were found in 39 lung cancer cell lines. Timmer et al (1999) using SSCP analysis of 16 lung cancer cell lines found a single presumably neutral mutation only in RBM5. However, by RT -PCR in the same study it was demonstrated the existence of two alternative splice variants of RBM6, one including and one excluding exon 5, in both normal lung tissue and lung cancer cell lines.…”

Section: Rbm5 and Rbm6mentioning

confidence: 99%

Tumor suppressor genes on chromosome 3p involved in the pathogenesis of lung and other cancers

Zabarovsky¹,

2002

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Loss of heterozygosity (LOH) involving several chromosome 3p regions accompanied by chromosome 3p deletions are detected in almost 100% of small (SCLCs) and more than 90% of non-small (NSCLCs) cell lung cancers. In addition, these changes appear early in the pathogenesis of lung cancer and are found as clonal lesions in the smoking damaged respiratory epithelium including histologically normal epithelium as well as in epithelium showing histologic changes of preneoplasia. These 3p genetic alterations lead to the conclusion that the short arm of human chromosome 3 contains several tumor suppressor gene(s) (TSG(s)). Although the first data suggesting that 3p alterations were involved in lung carcinogenesis were published more than 10 years ago, only recently has significant progress been achieved in identifying the candidate TSGs and beginning to demonstrate their functional role in tumor pathogenesis. Some of the striking results of these findings has been the discovery of multiple 3p TSGs and the importance of tumor acquired promoter DNA methylation as an epigenetic mechanism for inactivating the expression of these genes in lung cancer. This progress, combined with the well known role of smoking as an environmental causative risk factor in lung cancer pathogenesis, is leading to the development of new diagnostic and therapeutic strategies which can be translated into the clinic to combat and prevent the lung cancer epidemic. It is clear now that genetic and epigenetic abnormalities of several genes residing in chromosome region 3p are important for the development of lung cancers but it is still obscure how many of them exist and which of the numerous candidate TSGs are the key players in lung cancer pathogenesis. We review herein our current knowledge and describe the most credible candidate genes.

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A comparison of genomic structures and expression patterns of two closely related flanking genes in a critical lung cancer region at 3p21.3

Cited by 45 publications

References 13 publications

3p21.3 Tumor Suppressor Gene H37/Luca15/RBM5 Inhibits Growth of Human Lung Cancer Cells through Cell Cycle Arrest and Apoptosis

3p21.3 Tumor Suppressor Gene H37/Luca15/RBM5 Inhibits Growth of Human Lung Cancer Cells through Cell Cycle Arrest and Apoptosis

LUCA-15 suppresses CD95-mediated apoptosis in Jurkat T cells

Tumor suppressor genes on chromosome 3p involved in the pathogenesis of lung and other cancers

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