Activation of the c-mos oncogene in a mouse plasmacytoma by insertion of an endogenous intracisternal A-particle genome.

Abstract

The activation of the cellular oncogene c-mos in mouse plasmacytoma XRPC24 was found to result from the insertion of a 4.7-kilobase-pair cellular DNA element, within the cmos coding region. The element terminates on both sides with a direct repeat of around 335 nucleotides. The repeat as well as internal sequences of the element show strong homology to endogenous intracisternal A-particle (LAP) genes. The LAP genome integrated within c-mos in a headto-head (5' to 5') configuration. This juxtapositioned the LAP 5' long terminal repeat next to the bulk of the oncogene's coding region and shifted c-mos 5' coding and flanking sequences to a position further upstream. The significance of several aspects of this activation and transposition event is discussed.c-mos is a member of the family of cellular sequences, termed onc genes, which possess the potential to become malignant through incorporation into the genome of retroviruses (1) or by undergoing alterations within the cell (2). c-nos is the progenitor of the transforming information (v-mos) in Moloney murine sarcoma virus. The virus is presumably a recombinant between Moloney murine leukemia virus and the c-nos gene of BALB/ c mice (3, 4). c-and v-mos are composed of nearly identical sequences over their coding region, with the exception that cmos contains 21 additional codons at the 5' terminus, substituted in v-mos with 5 codons derived from viral helper sequences (5, 6). A Mr 37,000 protein identified within virus-infected cells (7) is encoded by the 374 codons of v-mos and presumably triggers cellular malignant transformation. No homologous protein coded by c-mos has been detected in normal cells.In a recent study (8) we described the rearrangement of the c-mos gene in mouse plasmacytoma XRPC24. Sequences from the 5' region of the gene, including 264 nucleotides of the presumed mos coding sequence as well as 5' flanking DNA, were substituted with a unique DNA. This rearrangement was accompanied by the appearance of mos transcripts in the tumor. Moreover, the molecularly cloned rearranged gene (termed rcmos), unlike its normal counterpart, induced transformed foci upon transfection into NIH/3T3 monolayers.More recently it was shown (9) that a 0.35-kilobase-pair (kbp) segment of the unique DNA, immediately adjacent to the junction point with c-mos sequences retained in rc-mos, had 88% sequence homology with the long terminal repeat (LTR) of an endogenous genetic element molecularly cloned from a library of mouse DNA (10). This element is a member of a family of highly reiterated endogenous mouse genes [intracisternal A particle (IAP) genes] homologous to the RNA of IAPs. The latter are noninfectious retrovirus-like structures found regularly in early mouse embryos (11-13) and present abundantly in every mouse plasmacytoma (14) and other mouse tumors (15).The association between an IAP LTR and the rearranged cellular mos was of considerable interest because it constituted one example of activation of a cellular oncogene by a mechanism involving relocat...

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

“…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).…”

Unusual long target duplication by insertion of intracisternal A‐particle element in radiation‐induced acute myeloid leukemia cells in mouse

“…Indeed, several established tumor cell lines have tumorigenic features generated at least in part by IAP element-derived activation of limited number of genes for c-mos [12] [24]. Heidemann determined the efficiency of retrotransmission by IAP element as 1.5 x 10 -6 per cell per generation in a teratocarcinoma cell line [25].…”

“…Additionally, an unusual long direct repeat of mouse DNA of 82 bp in length was generated at the insertion site of the lAP element, although the target duplication is no more than 6 bp in length in all the reported sequences suggesting a retroviral-like integration mechanism [3,5,6,8,[11][12][13][14][15][16][17][18][19]. The long target duplication may reflect a specific event which occurs during radiation-induced leukemogenesis.…”

"Retroposon" insertion into the cellular oncogene c-myc in canine transmissible venereal tumor.

“…High molecular weight cellular DNA and phage DNA were digested with restriction enzymes (New England Biolabs) in various combinations. Electrophoresis of agarose gels, blotting, and hybridization to nick-translated probes were performed as described (17)(18)(19). Poly(A)-rich RNA was electrophoresed and blotted as described by Thomas (34).…”

“…Major mechanisms implicated in the induction of the transforming activity of cellular oncogenes are (i) integration of a retroviral genome ih the vicinity of a cellular oncogene and consequent increase in the oncogene's level of expression (2-4); (ii) generation of a point mutation in the oncogene coding region leading to the formation of an altered gene product (5)(6)(7)(8); (iii) gene amplification, by which the oncogene copy number may increase as much as 60-fold (9)(10)(11)(12); and (iv) oncogene translocation to another chromosome (13)(14)(15)(16). Our work has provided an example of oncogene activation by yet a different process: the integration of an endogenous retrovirus-like DNA element (identified as an intracisternal A particle or IAP genome) within the coding region of the oncogene c-mos in mouse plasmacytomas XRPC 24 and NSI (17)(18)(19). The rearranged c-mos gene of XRPC 24 is actively transcribed and has transforming activity (17), suggesting some role for activated c-mos in the progression of XRPC 24 tumor.…”