The v-myc oncogene - Nature

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v-myc is the viral homolog of c-myc transduced by several acute transforming retroviruses, many of which encode this gene as a Gag-Myc fusion protein. The v-.
Oncogene (1999) 18, 2997 ± 3003 ã 1999 Stockton Press All rights reserved 0950 ± 9232/99 $12.00 http://www.stockton-press.co.uk/onc

The v-myc oncogene Clement M Lee1 and E Premkumar Reddy*,1 1

Fels Institute for Cancer Research and Molecular Biology, School of Medicine, Temple University, 3307 North Broad Street, Philadelphia, Pennsylvania, PA 19140, USA

v-myc is the viral homolog of c-myc transduced by several acute transforming retroviruses, many of which encode this gene as a Gag-Myc fusion protein. The vmyc oncogene can transform several lineages of mammalian and avian cells either alone or in cooperation with other oncogenes. While the Gag portion of the Gag-Myc fusion protein and the nuclear localization signal each appear to be dispensable for transformation, the N- and C-termini of the Myc sequence have been found to be essential for transformation. All v-myc genes contain point mutations which seem to confer a greater potency to v-myc in the process of transformation, proliferation, and apoptosis. In v-myctransformed myelomonocytic cells, secondary events occur, such as the expression of colony stimulating factor-1 (CSF-1) which play a critical role in immortalization and subsequent tumor progression. Inhibition of the autocrine loop of CSF-1 was found to induce apoptosis in the immortalized cells. While overexpression of v-Myc blocks terminal di€erentiation of hematopoietic cells, this is not sucient to block the di€erentiation of certain neural and skeletal muscle cells. Recent developments on the e€ects of v-myc on cell growth, transformation, di€erentiation and apoptosis are discussed in this review. Keywords: v-myc; gag-Myc; transformation; proliferation; apoptosis; di€erentiation

Introduction The v-myc oncogene was ®rst identi®ed as the transforming element of the acute transforming retrovirus MC29 which was isolated in 1964 from a chicken with spontaneous myelocytomatosis (Ivanov et al., 1964). The disease induced by this virus is characterized by the formation of foci of eosinophilic promyelocytes and metamyelocytes in bone marrow. This virus was also found to cause endotheliomas, sarcomas as well as liver and kidney carcinomas (Table 1). Following the advent of recombinant DNA techniques, the viral genome was cloned and the sequence of the v-myc gene was elucidated (Alitalo et al., 1983; Reddy et al., 1983; Watson et al., 1983). Later, the v-myc sequence was found to occur in four other independent retroviral isolates CMII, MH2, OK10 and FTT (Doggett et al., 1989; Hay¯ick et al., 1985; Kan et al., 1984; Walther et al., 1985), which cause di€erent neoplastic diseases in their hosts (Table 1).

*Correspondence: E Premkumar Reddy

MC29 is an acute transforming, replication defective virus in which part of gag, all of pol, and a large portion of env sequences are replaced by the hostderived myc sequence. The transforming protein encoded by this viral genome is a Gag-Myc fusion protein consisting of 452 N-terminal residues encoded by the 5' end of gag, linked to seven amino acid residues encoded by the 5' untranslated region of cmyc, followed by 416 amino acid residues encoded by exons 2 and 3 of chicken c-myc (Reddy et al., 1983) (Figure 1). CMII also encodes a similar Gag-Myc fusion protein. However, OK10 encodes two transforming Myc proteins from its genomic and subgenomic transcripts. The subgenomic transcript is spliced from a known donor sequence at the sixth gag codon and an acceptor sequence in the cellular intron sequence 5' to the v-myc coding sequence. Similarly, FTT is predicted to encode two transforming Myc proteins from its genomic and subgenomic transcripts (Figure 1). MH2 is di€erent from the other retroviruses since it encodes two oncogenes, vmyc and v-mil, the latter of which shares homology with murine v-raf and c-raf genes (Sutrave et al., 1984). v-myc and cell transformation Since the discovery of v-myc in 1983, ample information has been gathered on its ability to transform cells. When primary chicken embryonic ®broblasts are infected with MC29, cells are morphologically transformed and become refractile in shape due to a complete collapse of the actin network. These transformed cells exhibit a higher growth rate and saturation density, accompanied by an ability to grow in semisolid medium (Ramsay et al., 1990). When vmyc is overexpressed in bone marrow cells or early hematopoietic precursor cells, cell lines are established at varying stages of myelomonocytic di€erentiation ranging from myeloblasts to monocytes (Chisholm et al., 1992; Pirami et al., 1991) which readily form tumors in syngeneic mice (Chisholm et al., 1992). While v-myc readily transforms chicken embryonic ®broblasts and avian and murine hematopoietic cells, it shows little or no transforming activity in primary adrenocortical cells (MacAuley and Pawson, 1988). These cells show similar resistance to transformation by v-src. However, co-expression of both v-src and vmyc oncogenes in these cells results in an increase in the formation of foci which exhibit serum- and anchorage-independent growth. Similarly, v-myc can potentiate the transformation activities of the BCR ± ABL oncogene in Rat-1 cell, and the v-ras oncogene in murine bone marrow cell and the rat embryonic ®broblasts (Land et al., 1983; Lugo and Witte, 1989;

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Schwartz et al., 1986). It is interesting that v-myc can co-operate qualitatively with a second oncogene, v-raf,

Table 1 Pathogenicity of MC29 family viruses Virus

Host

Country and year of isolation

MC29

avian

Bulgaria, 1964

CMII OK10 FTT MH2

avian avian feline avian

Germany, 1964 Finland, 1975 USA, 1969 UK, 1927

Neoplasm induced myelocytomatosis, endothelioma, sarcoma, liver/kidney carcinomasa myelcytomatosisb carcinomasc T-cell lymphomad monocytic leukemia, liver/kidney carcinomas, thymus lymphoma, sarcomae

a Beard et al., 1975, 1976; BeÂchade et al., 1988; Enrietto et al., 1983; Mladenov et al., 1967. bLoÈliger, 1964; LoÈliger and Schubert, 1966. c Hortling, 1978; Oker-Blom et al., 1978. dLevy et al., 1984; Mullins et al., 1984; Neil et al., 1984. eAlexander et al., 1979; BeÂchade et al., 1988; Graf et al., 1986; Palmieri and Vogel, 1987

to transform lymphoid cells. v-raf and v-myc can independently yield transformed pre-B cell lines from bone marrow cells under conditions which allow growth of myeloid and lymphoid cells. However, when both oncogenes are co-expressed in bone marrow cells, mature B cells and mature macrophage clones emerge (Principato et al., 1990) suggesting that v-myc can a€ect lineage determination and the stage of di€erentiation of hematopoietic cells. The MH2 virus expresses both v-myc and v-mil, which can cooperate in transformation in vitro and in vivo. v-mil can induce proliferation of quiescent neuroretina cells, whereas v-myc has no e€ect on these cells. However, these cells are transformed when both the genes are co-expressed (BeÂchade et al., 1985). v-mil has also been shown to transform chicken embryonic ®broblasts (Palmieri and Vogel, 1987). The infected cells exhibit transformed morphology and increased capability of growth in low serum conditions. However, these cells are less ecient in inducing foci and growing in semisolid medium compared with

Figure 1 Proviral genomes and transforming proteins of the MC29 family viruses. The v-myc DNA and encoded protein sequences are shown in ®lled and hatched boxes, respectively. The v-Myc proteins of FTT are predicted from their genomic and subgenomic transcripts (Doggett et al., 1989)

The v-myc oncogene CM Lee and EP Reddy

the MH2-infected cells. When bone marrow cells are infected with MH2, transformed macrophages are derived (Graf et al., 1986). Deletion analysis shows that v-myc stimulates cell proliferation, while v-mil induces the production of chicken myelomonocytic growth factor (cMGF) to abolish the growth factor requirement. Similar results are obtained using temperature-sensitive mutants of MH2 (von Weizsacker et al., 1986). In vivo, the MH2 virus eciently induces monocytic leukemia and liver tumors, whereas viruses expressing v-mil or v-myc do not (Graf et al., 1986). Moreover, the v-mil expressing virus induces ®brosarcoma (BeÂchade et al., 1988). Domains for transformation MC29 and CMII viruses express v-Myc as part of the Gag-Myc fusion proteins (Reddy et al., 1983; Walther et al., 1985). The Gag fusion part seems to be unnecessary for transformation as a variant of MC29 with the deletion of the entire Gag portion still gives rise to tumors (Shaw et al., 1985). However, no proper experiment has been conducted to date to compare the relative transformation activities of v-Myc proteins with and without the whole Gag fusion part. Moreover, studies with the avian retrovirus FH3, originally isolated after injection of a 10-day-old chick embryo with avian leukosis virus, suggest a modulatory role for the gag sequences (Chen et al., 1989). Thus, the FH3 viral genome codes for a protein of 145 kDa, which is larger than that of MC29 and contains almost the entire retroviral gag gene. In contrast to the other gagmyc avian retroviruses, FH3 fails to transform ®broblasts in vitro, although it can transform macrophages both in vitro and in vivo. After passage of FH3 in ®broblast cultures, a virus (FH3L) that is capable of rapidly transforming ®broblasts was isolated which encodes a smaller Gag-Myc fusion protein. Sequencing of an FH3L molecular clone revealed a 212-amino-acid deletion within the Gag portion. Using FH3/FH3L recombinants, Tikhonenko and Linial (1992) could demonstrate that the ®broblast transformation activity directly correlated with the presence of this deletion in the gag region. Moreover, the addition of the Gag sequence deleted from FH3L to the MC29 oncoprotein signi®cantly reduced its transforming activity as measured by focus assay. These data suggest that the C-terminal segment of Gag attenuates the oncogenic potential of Gag-Myc fusion proteins. The essential domains of v-Myc for transformation are mapped to its N-terminal (amino acids 1 ± 137) and C-terminal (amino acids 244 ± 410) regions which correspond to the transregulatory domain and the basic ± helix ± loop ± helix ± leucine zipper (B/HLH/LZ) domain, respectively (Farina et al., 1992; Min et al., 1993; Min and Taparowsky, 1992). The B/HLH/LZ domain is shown to associate with Max, which is required for v-Myc-mediated transformation (Min et al., 1993). The transregulatory domain may be involved in interacting with protein factors that are important for transformation. These putative factors may be cell-type speci®c because deletions within the transregulatory domain either completely abolish or highly compromise the transformation abilities in chicken embryo fibroblasts, but not in macrophages (Farina et al., 1992).

Mutation analysis of v-myc has resulted in a surprising observation which suggests that the nuclear localization signal of this protein is dispensable for ®broblast transformation (Min et al., 1993; Tikhonenko et al., 1993). The mutants lacking the nuclear localization signal were found to be as transforming as v-myc and as can be expected, the mutant proteins were found to localize mainly in the cytoplasm. Small amounts of mutant Myc could still be found in the nucleus, probably, because of the secondary nuclear localization signals, which weakly target v-Myc to the nucleus (Dang and Lee, 1988; Stone et al., 1987). Tikhonenko et al. (1993) estimated that only about 5% of the mutant protein could be detected in the nucleus which was less than the endogenous c-Myc present in these cells. Consequently, only a small fraction of Max was associated with Myc and the subcellular distribution of Max was not altered. Complete transformation by this mutant suggests that production of enough vMyc to tie up all cellular Max is not needed for transformation. These results could be interpreted to suggest that small amounts of the mutant v-Myc in the nucleus is sucient to transform simply due to its powerful growth-promoting activity. Alternatively, it could also be argued that the cytoplasmic mutant of vMyc transforms cells by sequestering negative-acting Myc-associated nuclear factors, such as Bin1 or the Rb-like protein p107, in the cytoplasm, or by interacting with some cytoplasmic factors involved in transformation. Mechanisms of oncogenic activation Several substitution mutations are observed among vMyc proteins that di€er from that of c-Myc (one for CMII, two for OK10, 27 for MH2, three for FTT with two deletions at C-terminus, and ®ve or seven for MC29 depending on the isolate) (Alitalo et al., 1983; Doggett et al., 1989; Hay¯ick et al., 1985; Kan et al., 1984; Reddy et al., 1983; Walther et al., 1985; Watson et al., 1983). Most of the mutations occur in the Nand C-termini of v-Myc, mapping to the domains required for transformation. Among these, mutation of Thr61 is most common. Domain swapping experiments were performed between c-Myc and v-Myc to evaluate the importance of these mutations (Frykberg et al., 1987; Symonds et al., 1989). Results from these studies show that v-Myc, c-Myc and the chimeric mutants can transform embryonic ®broblasts and establish transformed monocytes from bone marrow cells. Results of these experiments suggest that v-myc is the most potent transforming gene, followed by the chimeric mutants, while the c-myc gene is the least potent transforming agent. This suggests that the mutations in the N- and C-termini are equally important in potentiating the transformation activity of v-myc. It is interesting to note that monocytes transformed by v-myc, but not cmyc nor the chimeric mutants, are capable of progressing to an immortal, growth factor-independent phenotype in vitro (Baumbach et al., 1986; Symonds et al., 1989). This suggests that mutations in either terminus, by themselves, while contributing to monocytic transformation eciency, are not sucient to induce immortalization and tumorigenicity. However, they may show synergism to accommodate

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secondary events for such progression. Since individual retroviruses encoding the v-myc oncogene exhibit a varying spectrum of mutations, it is possible that this variation accounts for the diversity of diseases caused by these di€erent retroviruses (Table 1). The frequent mutation spot Thr61, which is equivalent to Thr58 in human c-Myc, appears to play an important role in transformation since this mutation is often found in Burkitt's lymphomas (Albert et al., 1994). It is modi®ed in vivo by phosphorylation but also by O-linked N-acetylglucosamine (Chou et al., 1995; Henriksson et al., 1993; Pulverer et al., 1994), suggesting that Myc is negatively regulated by these post-translational modi®cations, and that the v-Myc protein escapes this negative regulation by virtue of mutation. v-Myc is also activated by deregulated expression. Endogenous c-Myc is under very tight transcriptional and translational regulation to ensure that its level is modulated according to the physiological needs of cells. However, di€erent mechanisms can deregulate the c-Myc level, such as retroviral transduction, viral integration, chromosomal translocation and gene ampli®cation (Spencer and Groudine, 1991; Zimmerman and Alt, 1990). All constitutively increase the steady-state levels of Myc. In case of retroviral transduction, Myc expression is driven by the retroviral long terminal repeat, which is not under normal cellular control. The importance of deregulation of v-Myc expression in transformation was demonstrated by placing the v-Myc gene under the control of an inducible metallothionein promoter (Bonham et al., 1991). When this vector was transfected into Rat-1 cells, it was observed that the transformation of these cells was graded with increasing zinc ion levels, and was reversible when zinc ion was removed from the medium demonstrating the dependence of transformation on the relative levels of v-Myc. Mechanisms of transformation and tumor progression Enhanced proliferation is the primary e€ect of v-Myc expression in transformation. Tikhonenko et al. (1995) created a conditional MC29 mutant expressing v-Myc as a fusion protein with the ligand binding domain of the glucocorticoid receptor and the Gag protein. This mutant, when expressed in quail embryo cells in culture, is capable of transformation only in the presence of glucocorticoids. All the transfectants were found to proliferate only in the presence of glucocorticoids and hormone deprivation was found to either slow down or stop cell proliferation. These results suggest that v-Myc is not only required to establish, but also to maintain the increased growth rate of transformed ®broblasts. However, when the cells were grown in the absence of glucocorticoids, all clones were found to remain viable for an extended period of time (more than 4 months) suggesting that their survival beyond the normal life span is not dependent on v-Myc activity, and enhanced proliferation and immortalization can be uncoupled. Furthermore, most clones did not exhibit a requirement for the presence of hormones to sustain anchorageindependent growth in soft agar, suggesting that

certain secondary events have sustained immortality and anchorage-independent growth independently of v-Myc. Nevertheless, none of these events can replace the need for v-Myc in proliferation control. Following transformation by v-Myc, secondary events occur to confer cells an immortal and tumorigenic phenotype. Monocyte transformation by the v-myc oncogene has been used to study myelomonocytic tumor progression in vitro (Stapleton et al., 1991; Symonds et al., 1989). Murine monocytes transformed by a recombinant retrovirus containing MC29 v-myc were found to exhibit a proliferative burst to days 28 ± 40 post-infection. Thereafter, growth slowed and cell number remained relatively static to days 80 ± 90 post-infection. During these periods, the growth and viability of the cells was dependent on the myelomonocytic growth factor, CSF-1. These cells were found to be polyclonal, non-immortal, and nontumorigenic in syngeneic mice. c-raf and c-fms (CSF-1 receptor) were induced in these cells at this stage. At days 80 ± 90 post-infection, a fresh round of proliferation occurred and growth was sustained allowing the establishment of cell lines. These cell lines were found to be monoclonal, immortal, growth-factor independent, and, in some cases, tumorigenic in syngeneic mice. They were shown to express CSF-1 in addition to c-raf, and c-fms. It is likely that CSF-1 expression is one of the secondary events which allows the cells to bypass the growth factor requirements in vitro. These results suggest that following transformation by v-myc, monocytes can progress in vitro to become growth factor independent and immortal, and that both monocyte transformation and immortalization can be dissociated from tumorigenicity. v-myc can also abrogate the interleukin-3 (IL-3) requirement for an IL-3-dependent early myeloid cell line FDC-P1 (Rapp et al., 1985). In the absence of IL3, IL-3-independent cell lines are obtained when FDCP1 cells are infected to express v-Myc. IL-3 is not detected to be secreted by the IL-3-independent cells and a neutralizing antibody against IL-3 fails to inhibit the growth of these cells. This shows that the cells do not develop an autocrine regulation to support their own growth requirements. In contrast, v-Myc may send the growth signals to compensate those delivered by IL-3 in these cells. Role of v-myc in proliferation, di€erentiation and apoptosis v-Myc, like c-Myc, can enhance cell proliferation. However, v-Myc is a stronger inducer of cell proliferation than c-Myc (Petropoulos et al., 1996). Thus, chicken embryonic ®broblasts subjected to ¯ow cytometric analysis exhibit a twofold higher percentage of cells in the S and G2/M phases of the cell cycle in v-Myc-infected cells compared to c-Myc-infected cells. At the same time, this analysis also shows that approximately 12 or 27% of the c-myc or v-myc infected cells, respectively, are undergoing apoptosis, while uninfected cells have only 3% apoptotic cells. This indicates that v-Myc is a stronger inducer of apoptosis than c-Myc. This concurrence of Mycmediated apoptosis and proliferation in a growing population may represent a phenomenon of primary

The v-myc oncogene CM Lee and EP Reddy

cells during the process of cellular transformation. The apoptotic function of myc might have been developed as a safeguard by nature to allow elimination of neoplastic cells with deregulated Myc expression. However, during the transformation process by v-Myc, the proliferative function out-balances the apoptotic function. This phenomenon also occurs in vivo in mice reconstituted with immature bone marrow cells infected with retroviruses expressing v-myc (Dolnikov et al., 1998). All mice develop leukemia with a short latency period (5 ± 11 weeks). In addition to hyperproliferation associated with elevated levels of proliferating cell nuclear antigen (PCNA), extensive apoptosis is found using TUNEL assay in all leukemic animals with p53 accumulating in the apoptotic cells. A key e€ector of p53 apoptotic activity, Bax, is also detected in cells undergoing apoptosis. These data show that v-Myc-mediated apoptosis cannot prevent leukemia development and hyperproliferation. When v-myc-transformed myelomonocytic cell lines are induced to undergo apoptosis by the addition of dexamethasone or dimethyl sulfoxide, the entry of cells into the apoptotic pathway appeared to be associated with the disruption of the CSF-1 autocrine loop (Dolnikov et al., 1996; Marthyn et al., 1998). The vmyc mediated apoptotic pathways appear to be dependent on the tumor suppressor p53 since coexpression of v-Myc and wild type p53 in the v-Myctransformed cells promotes apoptosis (Wang et al., 1993a). However, over-expression of Bcl-2 can protect v-Myc-transformed cells from apoptosis (Wang et al., 1993b), an observation that is consistent with the role of c-Myc in apoptosis and its relationship with p53 and Bcl-2 (Bissonnette et al., 1992; Evan et al., 1992; Hermeking and Eick, 1994; Sakamuro et al., 1995; Wagner et al., 1994). These results suggest that during the process of transformation, secondary events occur in v-myc expressing cells that lead to the inactivation of the apoptotic function of v-Myc. This appears to be achieved by inactivation of p53, overexpression of Bcl2, or other events. During di€erentiation of hematopoietic cells, endogenous c-myc levels decrease at the terminal stage (Ho€man-Liebermann and Liebermann, 1991). Like cMyc, v-Myc overexpression can block the terminal di€erentiation of the transformed cells (Chisholm et al., 1992; Larsson et al., 1988; Oberg et al., 1991). The vmyc-transformed myelomonocytic cell lines have been examined for their abilities to di€erentiate in response to external stimuli such as vitamin D3, retinoic acid, phorbol ester and lipopolysaccharide (LPS). Results from these studies show that v-myc transformed cells consistently fail to undergo terminal di€erentiation in the presence of these agents (Chisholm et al., 1992; Larsson et al., 1988; Oberg et al., 1991). Role of v-myc in transformation and di€erentiation of neural and skeletal muscle cells A number of studies have explored the e€ects of v-myc in non-hematopoietic cells. When primary sympathetic neurons are infected to express v-Myc, the cells gain enhanced survival/proliferation ability (Haltmeier and Rohrer, 1990) and appear to remain in their immature status. Similarly, a neuronal progenitor cell line can be

established by v-Myc under an inducible promoter from the cells of adult rat hippocampus (Hoshimaru et al., 1996). Upon suppression of the v-Myc expression, the cell line stops proliferating, begins to extend neurites, and expresses neuronal markers. These results show that v-Myc can confer hyperproliferative activity to these neural cells, and that a decrease in vMyc expression is sucient to make the proliferating cells exit cell cycle and enter the process of terminal di€erentiation. These ®ndings are in agreement with the role of v-Myc in the di€erentiation of myelomonocytic cells. On the other hand, rat neural crest cells immortalized by v-Myc can be induced to differentiate (Lo et al., 1991). Immortalized cells have the characteristics of peripheral glial progenitor cells and under serum-free conditions can di€erentiate to elongated, bipolar Schwann cells. This process can be inhibited by transforming growth factor-b1, which acts as a mitogen for these cells. At low frequency, some cells di€erentiate into sympathoadrenergic progenitor cells. Similarly, the v-Myc-immortalized progenitor cells from neonatal cerebellum are multipotent and can integrate into cerebellum in a nontumorigenic, cytoarchitecturally appropriate manner (Snyder et al., 1992). These cells di€erentiate into at least two neuronal types or into glia consistent with their sites of engraftment. These data show that cetain neural cells can be immortalized by v-Myc in a manner which does not block their ability to di€erentiate. The contradictory roles of v-Myc in neural di€erentiation may be due to the complexities of the di€erentiation programs in di€erent neural cells. Similarly, v-Myc-transformed muscle cells can still be induced to di€erentiate biochemically although myotube formation by fusion of the di€erentiated cells is prevented (Crescenzi et al., 1994). These results suggest that overexpression of Myc is insucient by itself to suppress the di€erentiation programs of all cell types. Summary and future perspectives In most cell types, v-myc-mediated transformation is associated with a block to terminal di€erentiation programs with a concomitant increase in the proliferative function of the transformed cells. At the same time, v-myc expression allows cells to attain higher saturation density and anchorage-independent growth, perhaps mediated by the accompanying reorganization of cytoskeleton as manifested by their transformed morphology. Secondary events occur, such as acquisition of CSF-1 autocrine stimulation, which lead to immortalization and tumorigenicity. Like c-Myc, vMyc can perform diverse functions with respect to transformation, proliferation, apoptosis, and differentiation. However, in many aspects, v-Myc is a stronger inducer of these diverse biochemical pathways than cMyc due to the potentiation by the substitution mutations. Recently, investigations have begun to identify the target genes of v-Myc by di€erential hybridization and mRNA di€erential display (Oberst et al., 1997; Tikhonenko et al., 1996). Hopefully, in the near future, we will have a better understanding on how

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v-Myc co-ordinates its diverse functions to transform cells by modulating gene expression. One especially interesting question is whether substitution mutations

of v-Myc lead to quantitative and/or qualitative changes in gene expression compared with c-Myc.

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