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. 1990 Jul;10(7):3535–3540. doi: 10.1128/mcb.10.7.3535

Conversion of differentiation inducer resistance to differentiation inducer sensitivity in erythroleukemia cells.

J Michaeli 1, Y B Lebedev 1, V M Richon 1, Z X Chen 1, P A Marks 1, R A Rifkind 1
PMCID: PMC360788  PMID: 1972544

Abstract

Hexamethylene bisacetamide (HMBA) is a potent inducer of differentiation of murine erythroleukemia cells (MELC). Commitment, the irreversible initiation of the program of terminal-cell differentiation, is first detected in HMBA-sensitive DS19-SC9 MELC in culture after 10 to 12 h of exposure to HMBA. Vincristine (VC)-resistant MELC derived from the DS19-SC9 MELC line display increased sensitivity to HMBA and become committed with little or no latent period. In the present study, we showed that the MELC line R1, which is resistant to HMBA-mediated differentiation, became sensitive to inducer if selected for a low level of VC resistance (less than 10 ng of VC per ml). Four independently derived VC-resistant cell lines from HMBA-resistant R1 cells, designated R1[VCR]a to R1[VCR]d, acquired sensitivity to HMBA and the accelerated kinetics of commitment that are characteristic of VC-resistant MELC derived from the parental DS19-SC9 cells. The calcium channel blocker verapamil suppresses the VC resistance of R1[VCR] cells but does not alter the accelerated response to HMBA. In R1[VCR] cells there was no detectable increase in the level of the 140-kilodalton P-glycoprotein. Transient inhibition of protein synthesis during the latent period delays inducer-mediated commitment of VC-sensitive DS19-SC9 MELC but does not alter the accelerated commitment kinetics of R1[VCR]a cells. Previously, we have reported evidence that protein kinase C beta (PKC beta) plays a role in HMBA-induced MELC differentiation and that compared with DS19-SC9 cells, R1 cells have a relatively low level and R1[VCR]a cells have a high level of PKC beta. These findings suggest that (i) acquisition of VC resistance overcomes the block acquired by R1 cells to HMBA-mediated differentiation; (ii) the accelerated kinetics of HMBA-induced commitment of VC-resistant MELC is not dependent on the verapamil-sensitive transport channel that is responsible, at least in part, for resistance to VC; (iii) in VC-resistant MELC, there is constitutive expression or accumulation of a protein required for HMBA-induced differentiation; and (iv) an elevated level of PKC beta activity may play a role in the altered response of R1[VCR] and other VC-resistant MELC to HMBA.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Burnette W. N. "Western blotting": electrophoretic transfer of proteins from sodium dodecyl sulfate--polyacrylamide gels to unmodified nitrocellulose and radiographic detection with antibody and radioiodinated protein A. Anal Biochem. 1981 Apr;112(2):195–203. doi: 10.1016/0003-2697(81)90281-5. [DOI] [PubMed] [Google Scholar]
  2. Chen Z., Banks J., Rifkind R. A., Marks P. A. Inducer-mediated commitment of murine erythroleukemia cells to differentiation: a multistep process. Proc Natl Acad Sci U S A. 1982 Jan;79(2):471–475. doi: 10.1073/pnas.79.2.471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Croop J. M., Gros P., Housman D. E. Genetics of multidrug resistance. J Clin Invest. 1988 May;81(5):1303–1309. doi: 10.1172/JCI113455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Draetta G., Luca F., Westendorf J., Brizuela L., Ruderman J., Beach D. Cdc2 protein kinase is complexed with both cyclin A and B: evidence for proteolytic inactivation of MPF. Cell. 1989 Mar 10;56(5):829–838. doi: 10.1016/0092-8674(89)90687-9. [DOI] [PubMed] [Google Scholar]
  5. Fibach E., Reuben R. C., Rifkind R. A., Marks P. A. Effect of hexamethylene bisacetamide on the commitment to differentiation of murine erythroleukemia cells. Cancer Res. 1977 Feb;37(2):440–444. [PubMed] [Google Scholar]
  6. Friend C., Scher W., Holland J. G., Sato T. Hemoglobin synthesis in murine virus-induced leukemic cells in vitro: stimulation of erythroid differentiation by dimethyl sulfoxide. Proc Natl Acad Sci U S A. 1971 Feb;68(2):378–382. doi: 10.1073/pnas.68.2.378. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Greenberger L. M., Williams S. S., Georges E., Ling V., Horwitz S. B. Electrophoretic analysis of P-glycoproteins produced by mouse J774.2 and Chinese hamster ovary multidrug-resistant cells. J Natl Cancer Inst. 1988 Jun 1;80(7):506–510. doi: 10.1093/jnci/80.7.506. [DOI] [PubMed] [Google Scholar]
  8. Gros P., Ben Neriah Y. B., Croop J. M., Housman D. E. Isolation and expression of a complementary DNA that confers multidrug resistance. Nature. 1986 Oct 23;323(6090):728–731. doi: 10.1038/323728a0. [DOI] [PubMed] [Google Scholar]
  9. Gusella J., Geller R., Clarke B., Weeks V., Housman D. Commitment to erythroid differentiation by friend erythroleukemia cells: a stochastic analysis. Cell. 1976 Oct;9(2):221–229. doi: 10.1016/0092-8674(76)90113-6. [DOI] [PubMed] [Google Scholar]
  10. Kartner N., Evernden-Porelle D., Bradley G., Ling V. Detection of P-glycoprotein in multidrug-resistant cell lines by monoclonal antibodies. 1985 Aug 29-Sep 4Nature. 316(6031):820–823. doi: 10.1038/316820a0. [DOI] [PubMed] [Google Scholar]
  11. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  12. Levenson R., Housman D. Developmental program of murine erythroleukemia cells. Effect of the inhibition of protein synthesis. J Cell Biol. 1979 Sep;82(3):715–725. doi: 10.1083/jcb.82.3.715. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Marks P. A., Chen Z., Banks J., Rifkind R. A. Erythroleukemia cells: variants inducible for hemoglobin synthesis without commitment to terminal cell division. Proc Natl Acad Sci U S A. 1983 Apr;80(8):2281–2284. doi: 10.1073/pnas.80.8.2281. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Marks P. A., Sheffery M., Rifkind R. A. Induction of transformed cells to terminal differentiation and the modulation of gene expression. Cancer Res. 1987 Feb 1;47(3):659–666. [PubMed] [Google Scholar]
  15. Melloni E., Pontremoli S., Damiani G., Viotti P., Weich N., Rifkind R. A., Marks P. A. Vincristine-resistant erythroleukemia cell line has marked increased sensitivity to hexamethylenebisacetamide-induced differentiation. Proc Natl Acad Sci U S A. 1988 Jun;85(11):3835–3839. doi: 10.1073/pnas.85.11.3835. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Melloni E., Pontremoli S., Michetti M., Sacco O., Cakiroglu A. G., Jackson J. F., Rifkind R. A., Marks P. A. Protein kinase C activity and hexamethylenebisacetamide-induced erythroleukemia cell differentiation. Proc Natl Acad Sci U S A. 1987 Aug;84(15):5282–5286. doi: 10.1073/pnas.84.15.5282. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Melloni E., Pontremoli S., Viotti P. L., Patrone M., Marks P. A., Rifkind R. A. Differential expression of protein kinase C isozymes and erythroleukemia cell differentiation. J Biol Chem. 1989 Nov 5;264(31):18414–18418. [PubMed] [Google Scholar]
  18. Morla A. O., Draetta G., Beach D., Wang J. Y. Reversible tyrosine phosphorylation of cdc2: dephosphorylation accompanies activation during entry into mitosis. Cell. 1989 Jul 14;58(1):193–203. doi: 10.1016/0092-8674(89)90415-7. [DOI] [PubMed] [Google Scholar]
  19. Peterson R. H., O'Neil J. A., Biedler J. L. Some biochemical properties of Chinese hamster cells sensitive and resistant to actinomycin D. J Cell Biol. 1974 Dec;63(3):773–779. doi: 10.1083/jcb.63.3.773. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Ramsay R. G., Ikeda K., Rifkind R. A., Marks P. A. Changes in gene expression associated with induced differentiation of erythroleukemia: protooncogenes, globin genes, and cell division. Proc Natl Acad Sci U S A. 1986 Sep;83(18):6849–6853. doi: 10.1073/pnas.83.18.6849. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Reuben R. C., Wife R. L., Breslow R., Rifkind R. A., Marks P. A. A new group of potent inducers of differentiation in murine erythroleukemia cells. Proc Natl Acad Sci U S A. 1976 Mar;73(3):862–866. doi: 10.1073/pnas.73.3.862. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Richon V. M., Ramsay R. G., Rifkind R. A., Marks P. A. Modulation of the c-myb, c-myc and p53 mRNA and protein levels during induced murine erythroleukemia cell differentiation. Oncogene. 1989 Feb;4(2):165–173. [PubMed] [Google Scholar]
  23. Sheffery M., Rifkind R. A., Marks P. A. Hexamethylenebisacetamide-resistant murine erythroleukemia cells have altered patterns of inducer-mediated chromatin changes. Proc Natl Acad Sci U S A. 1983 Jun;80(11):3349–3353. doi: 10.1073/pnas.80.11.3349. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Tsiftsoglou A. S., Gusella J. F., Volloch V., Housman D. E. Inhibition by dexamethasone of commitment to erythroid differentiation in murine erythroleukemia cells. Cancer Res. 1979 Oct;39(10):3849–3855. [PubMed] [Google Scholar]
  25. Tsuruo T. Reversal of acquired resistance to vinca alkaloids and anthracycline antibiotics. Cancer Treat Rep. 1983 Oct;67(10):889–894. [PubMed] [Google Scholar]
  26. Yamasaki H., Fibach E., Nudel U., Weinstein I. B., Rifkind R. A., Marks P. A. Tumor promoters inhibit spontaneous and induced differentiation of murine erythroleukemia cells in culture. Proc Natl Acad Sci U S A. 1977 Aug;74(8):3451–3455. doi: 10.1073/pnas.74.8.3451. [DOI] [PMC free article] [PubMed] [Google Scholar]

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