Coinfection with viruses carrying the v-Ha-ras and v-myc oncogenes leads to growth factor independence by an indirect mechanism.

Vogt, Marguerite; Lesley, Jayne; Bogenberger, J; Volkman, Sarah K.; Haas, Martin

doi:10.1128/mcb.6.10.3545

Cited by 22 publications

(14 citation statements)

References 15 publications

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“…A secondary progression event in addition to v-src expression was required for the cells to become factor independent. While the frequency and nature of this second event remain to be determined, it may involve gross karyotypic changes, as have been proposed to account for the indirect induction of growth factor independence by oncogenes in other systems (43). It seemed likely that a threshold level of v-src expression was required to enable the FDClsrc cells to undergo this second event and become factor independent, since the FDClsrc clone B5, which expressed the lowest amount of v-src RNA (Fig.…”

Section: Discussionmentioning

confidence: 99%

Nature and specificity of lymphokine independence induced by a selectable retroviral vector expressing v-src.

Overell¹,

Watson²,

Gallis³

et al. 1987

Mol. Cell. Biol.

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A murine retroviral vector, LSNLsrc, has been constructed and examined for its ability to induce growth factor independence in cells normally dependent on interleukin 2 (IL-2) or interleukin 3 (IL-3) for growth. The LSNLsrc vector coexpressed the v-src gene of Rous sarcoma virus and the neo gene from transposon Tn5, allowing infected cells to be selected on the basis of G418 resistance. The murine cell lines CTLL-2 and FD.C/1, which are dependent for growth on IL-2 and IL-3, respectively, were both readily infected with the LSNLsrc virus. LSNLsrc-infected, G418-resistant cultures of FD.C/1 cells were able to give rise to IL-3-independent progeny, but all G418-resistant CTLL-2 cells retained normal IL-2 dependence. The induction of IL-3 independence by v-src was not a direct event, since limiting dilution analysis of the LSNLsrc-infected FD.C/1 cells showed that most of them were IL-3 dependent, despite expression of v-src mRNA and active pp60v-src kinase. However, clones selected from this population in the presence of IL-3 were able to undergo a subsequent progression event and generate IL-3-independent progeny. The generation of factor-independent variants in the clonal cultures was a rare event, as witnessed by the death of most of the cells in each clone when IL-3 was withdrawn. Together, these data indicate that a secondary event, in addition to v-src expression, was required to generate IL-3-independent growth. No evidence was found for an autocrine mechanism of transformation involving IL-2, IL-3, interleukin 4, or granulocyte-macrophage colony-stimulating factor.

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Section: Discussionmentioning

confidence: 99%

Nature and specificity of lymphokine independence induced by a selectable retroviral vector expressing v-src.

Overell¹,

Watson²,

Gallis³

et al. 1987

Mol. Cell. Biol.

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“…The malignant clones selected in vivo may have undergone additional genetic changes that augment cell growth rate. Indeed, myc might promote further genetic changes, since v-myc appears to induce sister chromatid exchange and karyotypic abnormality (3,27). Any genetic changes would have to be subtle, however, since none of the H-MSV-or 3611-MSV-infected E,u-myc lines displayed gross karyotypic abnormalities even after several months in culture.…”

Section: Discussionmentioning

confidence: 99%

Oncogene cooperation in lymphocyte transformation: malignant conversion of E mu-myc transgenic pre-B cells in vitro is enhanced by v-H-ras or v-raf but not v-abl.

Ws¹,

Adams²,

Cory³

1989

Mol. Cell. Biol.

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Although transgenic mice bearing a c-myc gene controlled by the immunoglobulin heavy-chain enhancer (E,t) eventually develop B-lymphoid tumors, B-lineage cells from preneoplastic bone marrow express the transgene but do not grow autonomously or produce tumors in mice. To determine whether other oncogenes can cooperate with myc to transform B-lineage cells, we compared the in vitro growth and tumorigenicity of normal and Et-myc bone marrow cells infected with retroviruses bearing the v-H-ras, v-raf, or v-abl oncogene.The v-H-ras and v-raf viruses both generated a rapid polyclonal expansion of E,u-myc pre-B bone marrow cells in liquid culture and 10-to 100-fold more pre-B lymphoid colonies than normal in soft agar. The infected transgenic cells were autonomous, cloned efficiently in agar, and grew as tumors in nude mice. While many pre-B cells from normal marrow could also be induced to proliferate by the v-raf virus, these cells required a stromal feeder layer, did not clone in agar, and were not malignant. Most normal cells stimulated to grow by v-H-ras also cloned poorly in agar, and only rare cells were tumorigenic. With the v-abl virus, no more cells were transformed from E>-myc than normal marrow and the proportion of tumorigenic pre-B clones was not elevated. These results suggest that both v-H-ras and v-raf, but apparently not v-abl, collaborate with constitutive myc expression to promote autonomous proliferation and tumorigenicity of pre-B lymphoid cells.

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“…Progressed clones CI 1.1, CI 1.1.1.1, and CI 1.2.5.3, were obtained by coinfecting PXTL4 cells with retroviruses encoding v-my@K'O and v-Ha-ras [37,381. After infection, the cells were grown in methylcellulose cultures to select for growth factor-independent cells as previously described [37]. As has been described before [37,38], tumorigenic conversion by v-myc plus v-ras coinfection occurs via an indirect mechanism.…”

Section: Cell Linesmentioning

confidence: 99%

“…After infection, the cells were grown in methylcellulose cultures to select for growth factor-independent cells as previously described [37]. As has been described before [37,38], tumorigenic conversion by v-myc plus v-ras coinfection occurs via an indirect mechanism. Of the 12 growth factor-independent clones that we picked, three were determined to be independently derived due to specific integration of the myc and ras sequences on Southern blots.…”

Section: Cell Linesmentioning

confidence: 99%

“…We wished to know whether lymphoma-derived PXTL cell lines represent progenitors of fully tumorigenic progressed T-lymphoma cells. Since spontaneous progression of PXTLs to a fully tumorigenic phenotype has not been observed under normal culture conditions, we resorted to the use of retrovirally transduced oncogenes [37,38] to induce progression of PXTL cells to a growth factor-independent, fully tumorigenic phenotype.…”

Section: In Vitro Progression Of Pxtl Cells To Full Tumorigenicitymentioning

confidence: 99%

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Association of induction of a fully tumorigenic phenotype in murine radiation‐induced T‐lymphoma cells with loss of differentiation antigens, gain of CD44, and alterations in p53 protein levels

Gjerset

Arya

Volkman

et al. 1992

Molecular Carcinogenesis

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We investigated the mechanism of radiation induction of murine thymic lymphomas by studying the characteristics of primary x-ray-induced thymic lymphoma (PXTL) cell lines and of their oncogene-induced, progressed progeny. It is widely thought that proto-oncogene alterations are associated with the induction of murine lymphomas; however, few, if any primary murine radiation-induced lymphomas possess (proto-)oncogene alterations. Independently derived cell lines grown directly (i.e., without in vivo transplantation) from thymic lymphomas of irradiated C57BL/6 mice possess the properties of immortalized pre-T cells and lack many of the characteristics of "tumor cells". PXTL cells are poorly tumorigenic upon transplantation, do not clone in methylcellulose cultures, are growth factor dependent and autocrine, and lack consistent chromosome and oncogene abnormalities. However, the thymic lymphomas are malignant and cause the death of each afflicted mouse. PXTL cells expressed two immunologically distinct forms of the tumor suppressor protein p53 that have moderately increased stability (t1/2 = 1 h) when compared with p53 of normal splenic T lymphocytes. Early PXTL cells could progress in vitro to a fully tumorigenic phenotype after infection with retroviruses encoding the c-myc and v-ras oncogenes. Progressed T-lymphoma cells acquired growth factor independence, a highly transplantable and tumorigenic phenotype, and the ability to quantitatively clone in methylcellulose cultures. Progressed lymphoma cells coordinately downregulated the expression of five T-cell differentiation markers, upregulated the expression of CD44 (Pgp-1), and harbored vastly elevated levels of two immunologically distinct forms of p53. Our results suggest that the early thymic lymphomas consist of differentiation-inhibited, immortal pre-T cells that are precursors to progressed, fully tumorigenic T-lymphoma cells.

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Coinfection with viruses carrying the v-Ha-ras and v-myc oncogenes leads to growth factor independence by an indirect mechanism.

Cited by 22 publications

References 15 publications

Nature and specificity of lymphokine independence induced by a selectable retroviral vector expressing v-src.

Nature and specificity of lymphokine independence induced by a selectable retroviral vector expressing v-src.

Oncogene cooperation in lymphocyte transformation: malignant conversion of E mu-myc transgenic pre-B cells in vitro is enhanced by v-H-ras or v-raf but not v-abl.

Association of induction of a fully tumorigenic phenotype in murine radiation‐induced T‐lymphoma cells with loss of differentiation antigens, gain of CD44, and alterations in p53 protein levels

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