Skip to main content
SpringerLink
Log in

Differentiation of Myeloid Cell Lines Correlates with a Selective Expression of RIZ Protein

  • Published:
Molecular Medicine Aims and scope Submit manuscript

Abstract

Background

The retinoblastoma-interacting zinc-finger gene RIZ is expressed in two forms (RIZ1 and RIZ2) that differ for the presence near the N-terminus of RIZ1 of a conserved domain, defined PR (PRDI-BF1-RIZ homology), homologous to a similar domain present in other proteins recognized as tumor suppressor gene products. The RIZ1 form is usually absent or expressed at low levels in tumor cells, whereas RIZ2 is frequently expressed. We investigated a possible involvement of RIZ1 in differentiation control using a myeloid cell maturation model that is easily modulated by retinoids and other agents.

Materials and Methods

HL60 or NB4 cell lines or patients’ leukemic promyelocytes were treated with all-trans-retinoic acid or other agents to induce differentiation. RIZ gene expression was determined with reverse transcriptase polymerase chain reaction (RT-PCR) and RNase protection assay. Immunocytochemistry was performed to assess variation of the intracellular distribution of RIZ protein on all-trans-retinoic acid treatment. Forced expression of RIZ1 protein was obtained with a recombinant adenovirus containing RIZ1 cDNA.

Results

Treatment with retinoic acid induced a selective expression of RIZ1 in HL60 cell line. Retinoic acid effect was maximal at 7 days and correlated to the granulocytic differentiation of cells. A similar effect was obtained in retinoic acid-sensitive NB4 cell line or in patients’ leukemic promyelocytes, but not in the retinoic acid-resistant cell line NB4.007/6 or in the U937 cell line. Selective expression of RIZ1 was also induced by 12-O-tetradecanoyl-phorbol-13-acetate in the U937 and HL60 cell lines and by 1,25-dihydroxyvitamin D3 only in HL60 cells. In HL60 cells, RIZ1 was also induced by activation of a retinoid α receptor-independent maturation pathway based on retinoid X receptor agonist and protein kinase A synergism. In addition, retinoic acid produced a redistribution of the antigen within the nucleus in these cells. Forced expression of RIZ1 protein induced growth arrest and death of HL60 cells.

Conclusions

The correlation between the selective expression of RIZ1 induced by retinoic acid, 12-O-tetradecanoyl-phorbol-13-acetate, or 1,25-dihydroxyvitamin D3 and differentiation suggested that RIZ protein was involved in myeloid cell differentiation induced by these agents.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Buyse IM, Shao G, Huang S. (1995) The retinoblastoma protein binds to RIZ, a zinc-finger protein that shares an epitope with the adenovirus E1A protein. Proc. Natl. Acad. Sci. U.S.A. 92: 4467–4471.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Muraosa Y, Takahashi K, Yoshizawa M, Shibahara S. (1996) cDNA cloning of a novel protein containing two zinc-finger domains that may function as a transcription factor for the human heme-oxygenase-1 gene. Eur. J. Biochem. 235: 471–479.

    Article  CAS  PubMed  Google Scholar 

  3. Xie M, Shao G, Buyse I, Huang S. (1997) Transcriptional repression mediated by the PR domain zinc finger gene RIZ. J. Biol. Chem. 272: 26360–26366.

    Article  CAS  PubMed  Google Scholar 

  4. Shapiro VS, Lee P, Winoto A. (1995) Identification and cloning of the G3B cDNA encoding a 3′ segment of a protein binding to GATA-3. Gene 163: 329–330.

    Article  CAS  PubMed  Google Scholar 

  5. Buyse IM, Takahashi EI, Huang S. (1996) Physical mapping of the retinoblastoma interacting zinc finger gene RIZ to D1S228 on chromosome 1p36. Genomics 34: 119–121.

    Article  CAS  PubMed  Google Scholar 

  6. Chadwick RB, Jiang GL, Bennington GA, et al. (2000) Candidate tumor suppressor RIZ is frequently involved in colorectal carcinogenesis. Proc. Natl. Acad. Sci. U.S.A. 97: 2662–2667.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Liu L, Shao G, Steele-Perkins G, Huang S. (1997) The retinoblastoma interacting zinc finger gene RIZ produces a PR domain-lacking product through an internal promoter. J. Biol. Chem. 272: 2984–2991.

    Article  CAS  PubMed  Google Scholar 

  8. Fears S, Vignon C, Bohlander SK, Smith S, Rowley JD, Nucifora G. (1996) Intergenic splicing of MDS1 and EVI1 occurs in normal tissues as well as in myeloid leukemia and produces a new member of the PR domain family. Proc. Natl. Acad. Sci. U.S.A. 93: 1642–1647.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Turner CAJ, Mack DH, Davis MM. (1994) Blimp-1, a novel zinc finger-containing protein that can drive the maturation of B lymphocytes into immunoglobulin-secreting cells. Cell 77: 297–306.

    Article  CAS  PubMed  Google Scholar 

  10. Messika EJ, Lu PS, Sung YJ, et al. (1998) Differential effect of B lymphocyte-induced maturation protein (Blimp-1) expression on cell fate during B cell development. J. Exp. Med. 188: 515–525.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Chittka A, Chao MV. (1999) Identification of a zinc finger protein whose subcellular distribution is regulated by serum and nerve growth factor. Proc. Natl. Acad. Sci. U.S.A. 96: 10705–10710.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yang X, Huang S. (1999) PFM1 (PRDM4), a new member of the PR-domain family, maps to a tumor suppressor locus on human chromosome 12q23-q24.1. Genomics 61: 319–325.

    Article  CAS  PubMed  Google Scholar 

  13. He L, Yu JX, Liu L, et al. (1998) RIZ1, but not the alternative RIZ2 product of the same gene, is underexpressed in breast cancer, and forced RIZ1 expression causes G2-M cell cycle arrest and/or apoptosis. Cancer Res. 58: 4238–4244.

    PubMed  CAS  Google Scholar 

  14. Jiang GL, Liu L, Buyse IM, Simon D, Huang S. (1999) Decreased RIZ1 expression but not RIZ2 in hepatoma and suppression of hepatoma tumorigenicity by RIZ1. Int. J. Cancer 83: 541–546.

    Article  CAS  PubMed  Google Scholar 

  15. Abbondanza C, Medici N, Nigro V, et al. (2000) The retinoblastoma-interacting zinc-finger protein RIZ is a downstream effector of estrogen action. Proc. Natl. Acad. Sci. U.S.A. 97: 3130–3135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Grignani F, Fagioli M, Alcalay M, et al. (1994) Acute promyelocytic leukemia: from genetics to treatment. Blood 83: 10–25.

    PubMed  CAS  Google Scholar 

  17. Slack JL, Gallagher RE. (1999) The molecular biology of acute promyelocytic leukemia. Cancer Treat. Res. 99: 75–124.

    Article  CAS  PubMed  Google Scholar 

  18. Breitman TR, Collins SJ, Keene BR. (1981) Terminal differentiation of human promyelocytic leukemic cells in primary culture in response to retinoic acid. Blood 57: 1000–1004.

    PubMed  CAS  Google Scholar 

  19. Lo Coco F, Diverio D, Falini B, Biondi A, Nervi C, Pelicci PG. (1999) Genetic diagnosis and molecular monitoring in the management of acute promyelocytic leukemia. Blood 94: 12–22.

    PubMed  Google Scholar 

  20. Fanelli M, Minucci S, Gelmetti V, Nervi C, Gambacorti-Passerini C, Pelicci PG. (1999) Constitutive degradation of PML/RARalpha through the proteasome pathway mediates retinoic acid resistance. Blood 93: 1477–1481.

    PubMed  CAS  Google Scholar 

  21. Medici N, Abbondanza C, Nigro V, et al. (1999) Identification of a DNA binding protein cooperating with estrogen receptor as RIZ (retinoblastoma interacting zinc finger protein). Biochem. Biophys. Res. Commun. 264: 983–989.

    Article  CAS  PubMed  Google Scholar 

  22. Lee WS, Kao CC, Bryant GO, Liu X, Berk AJ. (1991) Adenovirus E1A activation domain binds the basic repeat in the TATA box transcription factor. Cell 67: 365–376.

    Article  CAS  PubMed  Google Scholar 

  23. Dignam JD, Lebovitz RM, Roeder RG. (1983) Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 11: 1475–1489.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Breitman T, Selonick S, Collins S. (1980) Induction of differentiation of the human promyelocytic leukemia cell line (HL-60) by retinoic acid. Proc. Natl. Acad. Sci. U.S.A. 77: 2936–2940.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Benoit G, Altucci L, Flexor M, et al. (1999) RAR-independent RXR signaling induces t(15;17) leukemia cell maturation. EMBO J. 18: 7011–7018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mori A, Higashi H, Hoshikawa Y, Imamura M, Asaka M, Hatakeyama M. (1999) Granulocytic differentiation of myeloid progenitor cells by p130, the retinoblastoma tumor suppressor homologue. Oncogene 18: 6209–6221.

    Article  CAS  PubMed  Google Scholar 

  27. Koeffler HP, Bar-Eli M, Territo MC. (1981) Phorbol ester effect on differentiation of human myeloid leukemia cell lines blocked at different stages of maturation. Cancer Res. 41: 919–926.

    PubMed  CAS  Google Scholar 

  28. McCarthy DM, San Miguel JF, Freake HC, Green PM, Zola H, Catovsky D, Goldman JM. (1983) 1,25-dihydroxyvitamin D3 inhibits proliferation of human promyelocytic leukaemia (HL60) cells and induces monocyte-macrophage differentiation in HL60 and normal human bone marrow cells. Leuk. Res. 7: 51–55.

    Article  CAS  PubMed  Google Scholar 

  29. Lin Y, Wong K, Calame K. (1997) Repression of c-myc transcription by Blimp-1, an inducer of terminal B cell differentiation. Science 276: 596–599.

    Article  CAS  PubMed  Google Scholar 

  30. Sood R, Talwar-Trikha A, Chakrabarti SR, Nucifora G. (1999) MDS1/EVI1 enhances TGF-beta1 signaling and strengthens its growth-inhibitory effect but the leukemia-associated fusion protein AML1/MDS1/EVI1, product of the t(3;21), abrogates growth-inhibition in response to TGF-beta1. Leukemia 13: 348–357.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank Dr. She Huang (The Burnham Institute, La Jolla, CA, USA) for providing the AdRIZ1 and AdGFP adenovirus vectors, Dr. Mirco Fanelli (Istituto Europeo di Oncologia, Milano, Italy) for the NB4.007/6 cell line, and Dr. Saverio Minucci (Istituto Europeo di Oncologia, Milano, Italy) for helpful discussions.

This investigation was supported by the Italian Ministry for University and Scientific and Technological Research.

Author information

Authors and Affiliations

  1. Istituto di Patologia generale ed Oncologia, Facoltà di Medicina e Chirurgia, Seconda Università degli studi di Napoli, Larghetto Sant’Aniello a Caponapoli, 2, I-80138, Naples, Italy

    Patrizia Gazzerro, Paola Bontempo, Ciro Abbondanza, Bruno Moncharmont MD, Ignazio Armetta, Ernesto Nola, Giovanni A. Puca & Anna Maria Molinari

  2. XIX Divisione di Ematologia, Azienda ospedaliera “A. Cardarelli”, Naples, Italy

    Ettore M. Schiavone & Mariacarla De Simone

  3. Istituto pluridisciplinare di Patologia generale, Università degli studi di Messina, Messina, Italy

    Nicola Medici

Authors
  1. Patrizia Gazzerro
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Paola Bontempo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ettore M. Schiavone
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ciro Abbondanza
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bruno Moncharmont MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ignazio Armetta
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nicola Medici
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mariacarla De Simone
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ernesto Nola
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Giovanni A. Puca
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Anna Maria Molinari
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bruno Moncharmont MD.

Additional information

P. G. and P. B. equally contributed to the work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gazzerro, P., Bontempo, P., Schiavone, E.M. et al. Differentiation of Myeloid Cell Lines Correlates with a Selective Expression of RIZ Protein. Mol Med 7, 552–560 (2001). https://doi.org/10.1007/BF03401861

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03401861

Keywords

Search

Navigation