Identification of a Candidate Tumor-Suppressor Gene Specifically Activated during Ras-Induced Senescence

Barradas, Marta; Gonos, Efstathios S.; Zebedee, Zoë; Kolettas, Evangelos; Petropoulou, Charikleia; Delgado, M. Dolores; León, Javier; Hara, Eiji; Serrano, Manuel

doi:10.1006/excr.2001.5434

Cited by 60 publications

(44 citation statements)

References 52 publications

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“…SERPINB5 has been reported as an upregulated gene in senescent dermal fibroblasts cells (Shelton et al, 1999) along with MT-1E, PLAU, PLAT, IL1B, IGFBP3 and superoxide dismutase (SOD2), which were all differentially expressed in our experiments (Table 1). Similarly, MT-2 and TFPI-2 (2.2-fold upregulated in DBC1 clone B) were identified as overexpressed during ras-induced senescence (Barradas et al, 2002). This may indicate that the changes we have observed are related to the reimposition by DBC1 of a stimulus that has the same effect as inappropriate oncogenic signalling and imposes features of a senescent-like growth arrest.…”

Section: Discussionsupporting

confidence: 54%

DBC1 re-expression alters the expression of multiple components of the plasminogen pathway

et al. 2005

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Deleted in bladder cancer 1 (DBC1) is a candidate gene for the bladder tumour suppressor locus at 9q33.1. The function of the gene is currently unknown but a crossspecies sequence comparison suggests an important role, as it is highly evolutionarily conserved. Here, we transfected a nonexpressing human bladder cancer cell line with a set of human DBC1 cDNA constructs. The effect on global expression patterns was assessed using cDNA microarrays. The cell clone with the lowest level of DBC1 expression showed induced expression of 26 genes including plasminogen activator inhibitor 2 (SERPINB5; 4.6-fold), heparin-binding EGF-like growth factor precursor (DTR; 4.2-fold), small proline-rich protein 2B (SPRR2B; 3.6-fold), metallothionein 1 isoforms (MT1B/ MT1A/MT-1F; from 2.9-to 3.2-fold), tissue-type plasminogen activator precursor (PLAT; 2.8-fold) and urokinase-type plasminogen activator precursor (PLAU; 2.7-fold). In clustering analysis, both PLAT and PLAU clustered with the functionally related urokinase plasminogen activator surface receptor (PLAUR; 1.9-fold). Furthermore, 14 human bladder tumours were analysed by real-time quantitative PCR using gene-specific primers for selected (n ¼ 20) genes. The expression levels of SERPINB5, PLAU, PLAUR and MT1 correlated with the DBC1 levels, suggesting previously unknown involvement of DBC1 in the urokinase-plasminogen pathway.

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Section: Discussionsupporting

confidence: 54%

DBC1 re-expression alters the expression of multiple components of the plasminogen pathway

et al. 2005

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“…However, irreversibly growth-arrested cells because of the effect of these reagents do not exhibit all features of "normal replicative senescence." For instance, H 2 O 2 -treated cells have long telomeres (48) and ras-induced senescent cells overexpress a set of genes that do not associate with normal in vitro aging (50). Similarly, our preliminary analysis indicates that proteasome inhibitortreated cells exhibit similar levels of expression of ␤ 2 , ␤ 5 , and S6b subunits as compared with non-treated cells.…”

Section: Discussionmentioning

confidence: 52%

Central Role of the Proteasome in Senescence and Survival of Human Fibroblasts

Chondrogianni

Stratford

Trougakos

et al. 2003

Journal of Biological Chemistry

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302

111

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Normal human fibroblasts undergo a limited number of divisions in culture and progressively they reach a state of irreversible growth arrest, a process termed as replicative senescence. The proteasome is the major cellular proteolytic machinery, the function of which is impaired during replicative senescence. However, the exact causes of its malfunction in these conditions are unknown. Using WI38 fibroblasts as a model for cellular senescence we have observed reduced levels of proteasomal peptidase activities coupled with increased levels of both oxidized and ubiquitinated proteins in senescent cells. We have found the catalytic subunits of the 20 S complex and subunits of the 19 S regulatory complex to be down-regulated in senescent cells. This is accompanied by a decrease in the level of both 20 S and 26 S complexes. Partial inhibition of proteasomes in young cells caused by treatment with specific inhibitors induced a senescence-like phenotype, thus demonstrating the fundamental importance of the proteasome for retaining cellular maintenance and homeostasis. Stable overexpression of ␤ 1 and ␤ 5 subunits in WI38 established cell lines was shown to induce elevated expression levels of ␤ 1 subunit in ␤ 5 transfectants and vice versa.

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“…Ris1 was identified in a screen looking for candidates participating in the protective, senescence-like, response elicited by oncogenic Ras in primary human fibroblasts (Barradas et al, 2002). To address the physiological function of Ris1, we first studied its expression pattern in mice.…”

Section: Discussionmentioning

confidence: 99%

“…Ris1 is highly upregulated in Ras-senescent human fibroblasts, not being induced in the same conditions if senescence is bypassed (i.e., in the concomitant presence of E1a). Moreover, Ris1 was not induced by other forms of senescence, such as replicative senescence, or by other forms of cellular stress or organismal aging, suggesting a specific association with Ras-induced senescence (Barradas et al, 2002). Importantly, the chromosomal location of Ris1 at 3p21.3 is highly provocative, because this region is frequently deleted in a variety of human solid cancers and, more specifically, Ris1 is contained in a short segment of 1.4 Mb mapped by other investigators for its tumor suppressive activity (Imreh et al, 2003;Petursdottir et al, 2004).…”

Section: Introductionmentioning

confidence: 92%

“…As part of our studies on the identification of new specific markers and putative mediators for Ras-induced senescence, we identified a novel gene Ris1 (Ras-induced senescence-1), which is specifically activated during OIS (Barradas et al, 2002). Ris1 is highly upregulated in Ras-senescent human fibroblasts, not being induced in the same conditions if senescence is bypassed (i.e., in the concomitant presence of E1a).…”

Section: Introductionmentioning

confidence: 99%

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Normal cellular senescence and cancer susceptibility in mice genetically deficient in Ras-induced senescence-1 (Ris1)

et al. 2006

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Oncogenic Ras triggers a permanent cell-cycle arrest known as oncogene-induced senescence (OIS) that constitutes a relevant tumor suppressor mechanism. Ris1 (Ras-induced senescence-1) is a novel gene that was identified in a screen as specifically upregulated during Ras-induced senescence, and that is located at a chromosomal region, 3p21.3, frequently lost in human cancer. Moreover, Ris1 is highly conserved in vertebrates, does not present paralogs, and its sequence does not reveal similarities with other proteins or domains. To analyse the physiological function of Ris1 and test its putative role as a tumor suppressor gene, we have generated mutant mice deficient for this gene. Ris1-null mice are viable, fertile, develop normally and do not display any obvious abnormalities. Of relevance, Ris1-deficient mice had a normal lifespan and did not exhibit predisposition to spontaneous tumors or to tumors induced by chemical carcinogens. Finally, Ris1-deficient embryonic fibroblasts were indistinguishable from wild-type cells regarding their proliferation properties, immortalization, senescence and oncogenic transformation. These findings do not support a role of Ris1 in tumor suppression or in OIS.

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Identification of a Candidate Tumor-Suppressor Gene Specifically Activated during Ras-Induced Senescence

Cited by 60 publications

References 52 publications

DBC1 re-expression alters the expression of multiple components of the plasminogen pathway

DBC1 re-expression alters the expression of multiple components of the plasminogen pathway

Central Role of the Proteasome in Senescence and Survival of Human Fibroblasts

Normal cellular senescence and cancer susceptibility in mice genetically deficient in Ras-induced senescence-1 (Ris1)

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