Activation of erythropoietin receptors by Friend viral gp55 and by erythropoietin and down-modulation by the murine Fv-2r resistance gene.

Hoatlin, Maureen E.; Kozak, Susan L.; Lilly, Frank; Chakraborti, Anuradha; Kozak, Christine A.; Kabat, David

doi:10.1073/pnas.87.24.9985

Cited by 85 publications

(52 citation statements)

References 35 publications

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“…The importance of Epo receptor signalling in the development of murine erythroleukemia is highlighted by studies in which infection of mice with recombinant retroviral vectors carrying genes encoding either Epo or a constitutively activated Epo receptor developed splenomegaly and polycythemia, which are similar to the early stages of Friend disease induced by FVP (17,32). Epo-independent, proerythroblast cell lines established from the spleens of mice infected with the activated Epo receptor virus had rearranged and inactivated both p53 alleles (32).…”

Section: Discussionmentioning

confidence: 99%

Growth suppression of Friend virus-transformed erythroleukemia cells by p53 protein is accompanied by hemoglobin production and is sensitive to erythropoietin.

Johnson¹,

Chung²,

Benchimol³

1993

Mol. Cell. Biol.

118

106

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The murine allele temperature-sensitive (ts) p53Val-13S encodes a ts p53 protein that behaves as a mutant polypeptide at 37°C and as a wild-type polypeptide at 32°C. This ts allele was introduced into the p53 nonproducer Friend erythroleukemia cell line DP16-1. The DP16-1 cell line was derived from the spleen cells of a mouse infected with the polycythemia strain of Friend virus, and like other erythroleukemia cell lines transformed by this virus, it grows independently of erythropoietin, likely because of expression of the viral gp55 protein which binds to and activates the erythropoietin receptor. When incubated at 32°C, DP16-1 cells expressing ts p53Val-135 protein, arrested in the G01G1 phase of the cell cycle, rapidly lost viability and expressed hemoglobin, a marker of erythroid differentiation. Erythropoietin had a striking effect on p53va'13.5-expressing cells at 32°C by prolonging their survival and diminishing the extent of hemoglobin production. This response to erythropoietin was not accompanied by down-regulation of viral gp55 protein.The p53 tumor suppressor gene is a common target for mutation in diverse human and animal tumors, and its loss or inactivation is, therefore, believed to play an important role in oncogenesis (reviewed in references 3, 18, and 29). A number of studies have examined the consequences of expressing a foreign wild-type p53 gene in transformed cells containing mutated endogenous p53 alleles. One common finding is that wild-type p53 protein has antiproliferative activity. While expression of a mutated p53 allele is tolerated in transformed cells, overexpression of wild-type p53 is not compatible with the continued growth of these cells and blocks cells in the G1 phase of the cell cycle (4,6,20,(36)(37)(38)50). Michalovitz et al. (38) have described a temperaturesensitive (ts) mutant murine p53 allele in which the predicted amino acid at position 135 is changed from alanine to valine. This allele was previously shown to cooperate with an activated ras gene to transform rat embryo fibroblasts at 37 but not at 320C (38). At 370C, cells expressing ras and the ts p53Val-135 allele were morphologically transformed. p53 protein was mainly cytoplasmic and bound to hsc70 protein, and it was predominantly in a conformation that was recognized by PAb240 (a monoclonal antibody that preferentially recognizes mutant p53 protein) but not by PAb246 (a monoclonal antibody that preferentially recognizes wild-type p53 protein). At 320C, p53 protein underwent a conformational change that rendered it more reactive with PAb246 than with PAb240. Moreover, binding to hsc70 protein was diminished, and p53 molecules localized to the nucleus. These striking changes in p53 protein were associated with growth arrest of the cells at the GJ1S border (13, 35). Cells already in the S or G2/M phase at the time of the temperature shift continued to traverse the cell cycle until they entered G1 and became blocked. Cells could be maintained at the low temperature in a viable but noncycling, GJG1-arrested state...

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Section: Discussionmentioning

confidence: 99%

Growth suppression of Friend virus-transformed erythroleukemia cells by p53 protein is accompanied by hemoglobin production and is sensitive to erythropoietin.

Johnson¹,

Chung²,

Benchimol³

1993

Mol. Cell. Biol.

118

106

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“…To date, three events have been identi®ed which contribute to generation of malignant erythroid cells (for a review, see Ben-David and Bernstein, 1991). The early stages of this process are associated with a polyclonal proliferation of nonleukemic erythroid progenitors caused by interaction of the SFFVencoded 55 kd fusion glycoprotein (gp55) with the erythropoietin receptor (Hoatlin et al, 1990;Li et al, 1990;Casadevall et al, 1991). Subsequently, clonal or oligoclonal erythroleukemic cells emerge.…”

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confidence: 99%

Deregulated expression of the PU.1 transcription factor blocks murine erythroleukemia cell terminal differentiation

et al. 1997

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Murine erythroleukemia (MEL) cells are transformed erythroid precursors that are blocked from completing the late stages of erythroid di erentiation. A frequent event in the generation of these malignant cells is deregulation of the hematopoietic-speci®c transcription factor PU.1 (Spi-1) by retroviral insertion of the spleenfocus-forming virus component of Friend virus. During chemically induced reinitiation of MEL cell terminal di erentiation, expression of PU.1 is rapidly downregulated, suggesting that PU.1 might interfere with processes required for terminal di erentiation of erythroid precursors. To investigate the role of PU.1 in erythroid di erentiation we transfected MEL cells with a PU.1 cDNA controlled by the eucaryotic translation elongation factor EF1a promoter. Deregulated expression of PU.1 blocked chemically induced di erentiation and terminal cell division. Deregulated expression of two other protooncogenes, c-myc and c-myb, also has been shown to block MEL di erentiation. We present evidence that PU.1 inhibits terminal di erentiation at an earlier step than c-Myc and c-Myb. Thus reinitiation of MEL cell terminal di erentiation appears to be controlled by an ordered program of turning o several protooncogenes. Down-regulation of PU.1 may be a very early step in this program.

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“…It seems that autocrine stimulation and additional events such as gene rearrangements or mutations are necessary to lead to a leukemic process. Indeed, in previous studies, overexpression of the Epo gene in normal murine hematopoietic cells through a retroviral construct, resulted in a proliferative syndrome and not to malignant transformation (Hoatlin et al, 1990;Villeval et al, 1992). A similar polycythemic disorder has been reported for mice transgenic for the human Epo gene (Semenza et al, 1989).…”

mentioning

confidence: 98%

Abnormal erythropoietin (Epo) gene expression in the murine erythroleukemia IW32 cells results from a rearrangement between the G-protein β2 subunit gene and the Epo gene

et al. 1997

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Activation of erythropoietin receptors by Friend viral gp55 and by erythropoietin and down-modulation by the murine Fv-2r resistance gene.

Abstract: The leukemogenic membrane glycoprotein (gp55) encoded by Friend spleen focus-forming virus appears to bind to erythropoietin receptors (EpoR) to stimulate erythroblastosis

Cited by 85 publications

References 35 publications

Growth suppression of Friend virus-transformed erythroleukemia cells by p53 protein is accompanied by hemoglobin production and is sensitive to erythropoietin.

Growth suppression of Friend virus-transformed erythroleukemia cells by p53 protein is accompanied by hemoglobin production and is sensitive to erythropoietin.

Deregulated expression of the PU.1 transcription factor blocks murine erythroleukemia cell terminal differentiation

Abnormal erythropoietin (Epo) gene expression in the murine erythroleukemia IW32 cells results from a rearrangement between the G-protein β2 subunit gene and the Epo gene

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