Functional evidence for a squamous cell carcinoma mortality gene(s) on human chromosome 4

Forsyth, Nicholas R.; Morrison, Vivienne; Craig, Nicky; Fitzsimmons, Sara A.; Barr, Nighean I.; Ireland, H. Elyse; Gordon, Katrina E.; Dowen, Sally E.; Cuthbert, Andrew; Newbold, Robert F.; Bryce, Steven D.; Parkinson, Eric K.

doi:10.1038/sj.onc.1205688

Cited by 10 publications

(10 citation statements)

References 48 publications

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“…A gene involved in cellular senescence was also postulated to lie in this region in squamous cell carcinoma and in HeLa cells . However, none of the genes analysed so far were mutated in cancer cells, which indicates that the relevant one remains to be discovered (Bluteau et al, 2002;Bryce et al, 2002;Forsyth et al, 2002). Nevertheless, taken together, these results suggest that FRA4F, like most other cloned CFS, contributes to the inactivation of a tumor suppressor gene.…”

Section: Discussionmentioning

confidence: 75%

Characterization of a conserved aphidicolin-sensitive common fragile site at human 4q22 and mouse 6C1: possible association with an inherited disease and cancer

et al. 2004

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Fragile sites are classified as common or rare depending on their occurrence in the populations. While rare sites are mainly associated with inherited diseases, common sites have been involved in somatic rearrangements found in the chromosomes of cancer cells. Here we study a mouse locus containing the ionotropic glutamate receptor delta 2 (grid2) gene in which spontaneous chromosome rearrangements occur frequently, giving rise to mutant animals in inbred populations. We identify and clone common fragile sites overlapping the mouse grid2 gene and its human ortholog GRID2, lying respectively at bands 6C1 and 4q22 in a 7-Mb-long region of synteny. These results show a third example of orthologous common sites conserved at the molecular level, and reveal an unexpected link between an inherited disease and an aphidicolin-sensitive region. Recurrent deletions of subregions of band 4q22 have been previously described in human hepatocellular carcinomas. This 15-Mb-long region appears precisely centered on the site described here, which strongly suggests that it also plays a specific role in hepatic carcinogenesis.

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Section: Discussionmentioning

confidence: 75%

Characterization of a conserved aphidicolin-sensitive common fragile site at human 4q22 and mouse 6C1: possible association with an inherited disease and cancer

et al. 2004

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“…If these mice are crossed with inducible NOS 2/2 mice, they no longer develop the cancer (10). The activity of GSNO reductase is also decreased in human hepatocellular carcinoma, possibly because of chromosome deletions and a loss of heterozygosity (LOH) at or near 4q23, similar to the deletions and LOH in human lung cancers (11)(12)(13)(14). Here, we show that human lung cancers also exhibit abnormal expression of GSNO reductase and decreased activity of GSNO reductase.…”

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confidence: 93%

S-Nitrosoglutathione Reductase in Human Lung Cancer

Marozkina¹,

Wei

Yemen³

et al. 2012

Am J Respir Cell Mol Biol

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S-Nitrosoglutathione (GSNO) reductase regulates cell signaling pathways relevant to asthma and protects cells from nitrosative stress. Recent evidence suggests that this enzyme may prevent human hepatocellular carcinoma arising in the setting of chronic hepatitis. We hypothesized that GSNO reductase may also protect the lung against potentially carcinogenic reactions associated with nitrosative stress. We report that wild-type Ras is S-nitrosylated and activated by nitrosative stress and that it is denitrosylated by GSNO reductase. In human lung cancer, the activity and expression of GSNO reductase are decreased. Further, the distribution of the enzyme (including its colocalization with wild-type Ras) is abnormal. We conclude that decreased activity of GSNO reductase could leave the human lung vulnerable to the oncogenic effects of nitrosative stress, as is the case in the liver. This potential should be considered when developing therapies that inhibit pulmonary GSNO reductase to treat asthma and other conditions. Keywords: lung cancer; S-nitrosoglutathione reductase; Ras Protein S-nitrosylation, the post-translational modification of a cysteine by the attachment of an NO group, is a regulated pathway that is responsible for a variety of signaling effects (1, 2). S-nitrosylation, caused both by exposure to exogenous nitrogen oxides and by the activity of nitric oxide synthase (NOS), is involved in the regulation of gene expression, cell division, and a spectrum of other processes in cell biology. For example, the S-nitrosylation of wild-type Ras by endothelial NOS (eNOS) is required for cell proliferation and tumor growth in a common model of tumorigenesis (3). Specifically, oncogenic K-Ras-GTP activates proteins to initiate human tumor growth. Of these proteins, only the phosphatidylinositol 3 kinase (PI3 kinase)/Akt pathway is indispensable for tumor maintenance (3). The essential Akt substrate for this process is eNOS. The activation of NOS, in turn, S-nitrosylates and activates wild-type (wt) H-Ras and N-Ras proteins at cysteine 118. Either the knockdown of eNOS or the mutation of wt Ras cysteine 118 (the site of S-nitrosylation) prevents the activation of Ras and the formation of tumors (3).Although the activation of NOS leads to wt Ras S-nitrosylation, the mechanism by which Ras can be denitrosylated is not known. As with phosphorylation/dephosphorylation coupling, the addition and removal of NO from cysteines are normally regulated in cell biology, and several enzymes serve as denitrosylases (1, 2, 4, 5). In the human airway, S-nitrosoglutathione (GSNO) reductase is an important enzyme responsible for denitrosylation (1,4,6,7). This highly conserved enzyme is traditionally regarded as an aldehyde dehydrogenase, although it is somewhat more efficient as GSNO reductase (5,8,9). Its relative redox activities depend on substrate concentration and the local nicotinamide adenine dinucleotide/ nicotinamide adenine dinucleotide reduced (NAD 1 /NADH) ratio. Our evidence suggests that decreased activity of GSNO re...

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“…Genetic analysis of the immortal phenotype has revealed several genetic alterations that are important to the process including the dysfunction of p53, INK4A and a gene on chromosome 3p that represses telomerase activity (Loughran et al, 1997;Parkinson et al, 1997). In addition, microcell-mediated monochromosome transfer (MMCT) experiments suggest that other cancer mortality genes may exist (Ning et al, 1991;Wang et al, 1992;Casey et al, 1993;Koi et al, 1993;Ogata et al, 1993;Hensler et al, 1994;Rimessi et al, 1994;Sandhu et al, 1994Sandhu et al, , 1996Sasaki et al, 1994;Uejima et al, 1995;England et al, 1996;Karlsson et al, 1996;Robertson et al, 1998;Cuthbert et al, 1999;Steenbergen et al, 2001;Forsyth et al, 2002). Loss of heterozygosity (LOH) at some of these chromosomal loci supports a role for the dysfunction of these putative mortality genes in the immortality of human SCCs (Loughran et al, 1997;Forsyth et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, microcell-mediated monochromosome transfer (MMCT) experiments suggest that other cancer mortality genes may exist (Ning et al, 1991;Wang et al, 1992;Casey et al, 1993;Koi et al, 1993;Ogata et al, 1993;Hensler et al, 1994;Rimessi et al, 1994;Sandhu et al, 1994Sandhu et al, , 1996Sasaki et al, 1994;Uejima et al, 1995;England et al, 1996;Karlsson et al, 1996;Robertson et al, 1998;Cuthbert et al, 1999;Steenbergen et al, 2001;Forsyth et al, 2002). Loss of heterozygosity (LOH) at some of these chromosomal loci supports a role for the dysfunction of these putative mortality genes in the immortality of human SCCs (Loughran et al, 1997;Forsyth et al, 2002). One of these is chromosome 6 (Loughran et al, 1997), which has also been shown to carry mortality genes for SV40-transformed human fibroblasts and human ovarian carcinoma cells mapping to 6q21-qter (Sandhu et al, 1994;Banga et al, 1997) and 6q14-q21 (Sandhu et al, 1996), respectively.…”

Section: Introductionmentioning

confidence: 99%

“…Previous investigations have used the technique of monochromosome transfer to induce proliferation arrest in human and rodent cancer lines (Ning et al, 1991;Wang et al, 1992;Casey et al, 1993;Koi et al, 1993;Ogata et al, 1993;Hensler et al, 1994;Rimessi et al, 1994;Sandhu et al, 1994Sandhu et al, , 1996Sasaki et al, 1994;Uejima et al, 1995;England et al, 1996;Karlsson et al, 1996;Banga et al, 1997;Robertson et al, 1998;Cuthbert et al, 1999;Steenbergen et al, 2001) and have attempted to identify the genes responsible by the extensive deletion analysis of segregant colonies that continue to proliferate (see for example, Rimessi et al, 1994;England et al, 1996;Karlsson et al, 1996;Robertson et al, 1998;Cuthbert et al, 1999;Forsyth et al, 2002). These studies have shown that, in some instances, the commonly deleted regions contain known antiproliferative genes (England et al, 1996;Robertson et al, 1998) or tumour suppressor genes (Cheng et al, 1998;Lo et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

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Human squamous cell carcinomas lose a mortality gene from chromosome 6q14.3 to q15

et al. 2003

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Normal human keratinocytes possess a finite replicative lifespan. Most advanced squamous cell carcinomas (SCCs), however, are immortal, a phenotype that is associated with p53 and INK4A dysfunction, high levels of telomerase and loss of heterozygosity (LOH) at several genetic loci, suggestive of the dysfunction of other mortality genes. We show here that human chromosome 6 specifically reduces the proliferation or viability of a human SCC line, BICR31, possessing LOH across the chromosome. This was determined by an 88% reduction in colony yield (Po0.001), following the reintroduction of an intact normal chromosome 6 by monochromosome transfer. Deletion analysis of immortal segregants using polymorphic markers revealed the loss of a 2.9 Mbp interval, centred on marker D6S1045 at 6q14.3-q15, in 6/ 19 segregants. Crucially, allelic losses of this region were not identified in control hybrids constructed between chromosome 6 and the BICR6 SCC cell line that is heterozygous for chromosome 6 and which showed no reduction in colony formation relative to the control chromosome transfers. This indicates that the minimally deleted region at D6S1045 is not the result of fragile sites, a recombination hot spot, or a feature of the monochromosome transfer technique. LOH of D6S1045 was found in 2/9 immortal SCC lines and was part of a minimally deleted region of line BICR19. Furthermore, allelic imbalance, consistent with LOH, was detected in 3/ 17 advanced SCCs of the tongue. These results suggest the existence of a suppressor of SCC immortality and tumour development at chromosome 6q14.3-q15, which is important to a subset of human SCCs.

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Functional evidence for a squamous cell carcinoma mortality gene(s) on human chromosome 4

Cited by 10 publications

References 48 publications

Characterization of a conserved aphidicolin-sensitive common fragile site at human 4q22 and mouse 6C1: possible association with an inherited disease and cancer

Characterization of a conserved aphidicolin-sensitive common fragile site at human 4q22 and mouse 6C1: possible association with an inherited disease and cancer

S-Nitrosoglutathione Reductase in Human Lung Cancer

Human squamous cell carcinomas lose a mortality gene from chromosome 6q14.3 to q15

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