Activation of the Transforming Potential of a Normal Cell Sequence: A Molecular Model for Oncogenesis

Blair, D. G.; Oskarsson, M; Wood, Theodore; McClements, William L.; Fischinger, Peter J.; Woude, GG Vande

doi:10.1126/science.7233190

Cited by 236 publications

(118 citation statements)

References 18 publications

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“…Overexpression of the gene causes transformation of NIH 3T3 cells and tumour growth in mice (Fefer et al, 1967;Blair et al, 1981). However, few studies have implicated c-MOS in human oncogenesis (Parkar et al, 1988;Stenman et al, 1991).…”

mentioning

confidence: 99%

Mutation analysis of the c-mos proto-oncogene in human ovarian teratomas

Foy

Gayther²,

Colledge³

et al. 1998

Br J Cancer

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Summary Female transgenic mice lacking a functional c-mos proto-oncogene develop ovarian teratomas, indicating that c-mos may behave as a tumour-suppressor gene for this type of tumour. We have analysed the entire coding region of the c-MOS gene in a series of human ovarian teratomas to determine whether there are any cancer-causing alterations. DNA from twenty teratomas was analysed by single-strand conformational analysis (SSCA) and heteroduplex analysis (HA) to screen for somatic and germline mutations. In nine of these tumours the entire gene was also sequenced. A previously reported polymorphism and a single new sequence variant were identified, neither of which we would predict to be disease-causing alterations. These results suggest that mutations in the coding region of the c-MOS gene do not play a significant role in the genesis of human ovarian teratomas.

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confidence: 99%

Mutation analysis of the c-mos proto-oncogene in human ovarian teratomas

Foy

Gayther²,

Colledge³

et al. 1998

Br J Cancer

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“…The v-mos gene of the Moloney murine sarcoma virus (Mo-MuSV) is a potent oncogene, as was demonstrated by both its ability to transform NIH3T3 cells (Blair et al, 1981;Lohka, 1989;Maller, 1990) and by its ability to induce ®brosarcomas in mice (Canaani et al, 1983). The mos protein is a serine/threonine protein kinase (Maxwell and Arlinghaus, 1985;Paules et al, 1992;Singh et al, 1988) that plays an essential role in the maturation of oocytes, where it is required for the activation of the maturation promoting factor (MPF) (de Moor and Richter, 1997;Yoshida et al, 2000).…”

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confidence: 99%

Double-stranded RNA-dependent protein kinase, PKR, down-regulates CDC2/cyclin B1 and induces apoptosis in non-transformed but not in v-mos transformed cells

et al. 2001

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The interferon (IFN)-induced, double stranded RNA (dsRNA)-activated serine/threonine kinase, PKR, is a potent negative regulator of cell growth when overexpressed in yeast or mammalian cells. Paradoxically, while it can function as a tumor suppressor and inducer of apoptosis, it is overexpressed in a variety of human cancers. To resolve this enigma, we established cell-lines that overexpress PKR in non-transformed and in v-mos transformed CHO cells. Overexpression of PKR suppressed the proliferation of CHO cells by inducing a transient G0/G1 arrest, followed by a delayed G2/M arrest, which attenuated cell cycle progression. These e ects were accompanied by early induction of p21/ WAF-1 and delayed downregulation of CDC2 and cyclin B1. Induction of proapoptotic activity of the ectopic PKR paralleled the onset of G2/M arrest in CHO cells. However, while transiently inducing p21/WAF-1, PKR did not impose G2/M arrest or apoptosis in v-mostransformed cells, nor was CDC2 or cyclin B1 downregulated in those cells. These ®ndings link the proapoptotic activity of PKR to the arrest of cell cycle at the G2/M phase. Consequently, the apoptotic activity of PKR could be counter-acted by an oncogene-like vmos that overrides the G2/M arrest induced by PKR. Oncogene (2001) 20, 8045 ± 8056.

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“…The first involves the incorporation of a cellular transforming gene, or oncogene, into a retrovirus so that it is expressed whenever the virus infects cells (1). The number of oncogenes in a mammalian genome is uncertain but is clearly more than one (2).…”

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confidence: 99%

Cloned endogenous retroviral sequences from human DNA.

Bonner¹,

O'Connell²,

Cohen

1982

Proc. Natl. Acad. Sci. U.S.A.

121

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We have screened a human DNA library using as probe a chimpanzee sequence that contains homology to the polymerase gene ofthe endogenous baboon virus. One set ofoverlapping clones spans about 20 kilobases and contains regions of DNA sequence homology to the gag p30, gag p15, and polymerase genes of Moloney murine leukemia virus. Furthermore, the spacings are the same as in Moloney virus between these sequences and a 480-nucleotide region that has the structural characteristics of a 3' copy of the long terminal repeat sequence. Hybridization of the cloned DNA to restriction digests of human DNA indicates that the human genome contains only two copies closely related to the sequence and 10 less closely related copies. This retroviral sequence appears to have been in its present chromosomal location prior to the divergence ofman and chimpanzee because the human and chimpanzee clones have 3-4 kilobases of identical 3' flanking sequence.Retroviruses have been shown to be capable ofinducing tumors by two basic mechanisms. The first involves the incorporation of a cellular transforming gene, or oncogene, into a retrovirus so that it is expressed whenever the virus infects cells (1). The number of oncogenes in a mammalian genome is uncertain but is clearly more than one (2). The second mechanism, demonstrated by the induction of bursal lymphomas in chickens by avian leukosis virus, involves the ability of the retroviruses to integrate a DNA copy ofthe viral genome into the chromosomal DNA of the host. In the rare case in which the viral DNA is integrated adjacent to an oncogene, the promoter sequences present in the termini of the integrated virus can activate the oncogene (3).As a result of the ability of the retroviruses to integrate into host DNA and, thus, become part of the host genome, many, if not most, mammals have accumulated tens or hundreds of integrated retroviral sequences. These endogenous viral sequences thus provide a reservoir of viral genes which might be activated by developmental or environmental factors including mutagens. These newly activated viruses then might induce tumors either by the mechanisms described above or through other mechanisms, such as inactivation of a critical gene by integration within the gene (4). Evidence that the activation of endogenous viral genes may be significant is provided by the observation that formation of a recombinant virus derived from two endogenous viruses is correlated with spontaneous leukemias in the AKR mouse (5), a strain with a high incidence of leukemia.The critical questions concerning retroviruses are whether they are involved in human carcinogenesis and, if so, to what degree. Attempts to answer these questions have been hampered by a dearth of human retroviruses. There is currently one human retrovirus (6). This virus is not an endogenous human retrovirus because related sequences are not found in normal human DNA (7). There is also a potential endogenous human retroviral sequence that was cloned from human DNA (8). To date this clone has b...

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Activation of the Transforming Potential of a Normal Cell Sequence: A Molecular Model for Oncogenesis

Cited by 236 publications

References 18 publications

Mutation analysis of the c-mos proto-oncogene in human ovarian teratomas

Mutation analysis of the c-mos proto-oncogene in human ovarian teratomas

Double-stranded RNA-dependent protein kinase, PKR, down-regulates CDC2/cyclin B1 and induces apoptosis in non-transformed but not in v-mos transformed cells

Cloned endogenous retroviral sequences from human DNA.

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