Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

The onset of p53-dependent apoptosis plays a role in terminal differentiation of human normoblasts

Oncogene volume 22, pages 4648–4655 (2003)Cite this article

Abstract

The p53 tumor suppressor gene was found to play a role in the differentiation of several tissue types. We report here that p53-dependent apoptosis plays a role in the final stages of physiological differentiation of normoblasts, resulting in nuclear condensation and expulsion without cell death. Blood samples of healthy newborns, cord blood as well as bone marrow, were analysed for apoptosis by TUNEL and p53 expression by immunostaining. While some samples exhibited simultaneously several distinct patterns of apoptosis, such as perinuclear, diffused nuclear or nuclear apoptotic bodies, others presented a single defined pattern. Overexpression of p53 protein was detected in normoblasts exhibiting either perinuclear or diffused nuclear p53, corresponding to the nuclear apoptotic pattern in the same sample. Similar results were also evident with colonies cultivated for 12–14 days in culture. Differentiated erythroid colonies exhibited overexpression of p53 and positive TUNEL staining only in the normoblasts. We further examined the state of caspase 3/7 and observed a decrease of this activated enzyme during erythroid differentiation in culture. This study suggests a novel role for apoptosis in normoblast differentiation where nuclear degradation occurs with a delay in the actual cell death. A pivotal role for the p53-dependent apoptosis in the erythroid lineage development is implied. However, this apoptotic process is not fully executed because of the exhaustion in caspase 3/7 and thus cells are diverted towards final stages of differentiation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  • Aljurf M, Ma L, Angelucci E, Lucarelli G, Snyder LM, Kiefer CR, Yuan J and Schrier SL . (1996). Blood, 87, 2049–2056.

  • Almog N and Rotter V . (1997). Biochim. Biopyhs. Acta, 1333, F1–F27.

  • Aloni-Grinstein R, Zan-Bar I, Alboum I, Goldfinger N and Rotter V . (1993). Oncogene, 8, 3297–3305.

  • Benito A, Silva M, Grillot D, Nunez G and Fernandez-Luna JL . (1996). Blood, 87, 3837–3843.

  • Betke K and Kleihauer E . (1967). Nature, 214, 188–189.

  • Chandrasekaran K, McFarland VW, Simmons DT, Dziadek M, Gurney EG and Mora PT . (1981). Proc. Natl. Acad. Sci. USA, 78, 6953–6957.

  • Frenkel J, Sherman D, Fein A, Schwartz D, Almog N, Kapon A, Goldfinger N and Rotter V . (1999). Oncogene, 18, 2901–2907.

  • Kastan M . (1996). BioEssays, 18, 617–619.

  • Kastan MB, Radin AI, Kuerbitz SJ, Onyekwere O, Wolkow CA, Civin CI, Stone KD, Woo T, Ravindranath Y and Craig RW . (1991). Cancer Res., 51, 4279–4286.

  • Kelley LL, Green WF, Hicks GG, Bondurant MC, Koury MJ and Ruley HE . (1994). Mol. Cell. Biol., 14, 4183–4192.

  • Kelley LL, Hicks GG, Hsieh FF, Prasher JM, Green WF, Miller MD, Eide EJ and Ruley HE . (1998). Oncogene, 17, 1119–1130.

  • Kelley LL, Koury MJ, Bondurant MC, Koury ST, Sawyer ST and Wickerman A . (1993). Blood, 82, 2340–2352.

  • Kollet O, Aviram R, Chebath J, ben-Hur H, Nagler A, Shultz L, Revel M and Lapidot T . (1999). Blood, 94, 923–931.

  • Koury MJ and Bondrant MC . (1990). Science, 248, 378–381.

  • Koury MK, Horne DW, Brown ZA, Pietenpol JA, Blount BC, Ames BN, Hard R and Koury ST . (1997). Blood, 89, 4617–4623.

  • Law JC, Ritke MK, Yalowich JC, Leder GH and Ferrel R . (1993). Leuk Res., 17, 1045–1050.

  • Louis JM, McFarland VW, May P and Mora PT . (1988). Biochim. Biophys. Acta, 950, 395–402.

  • Mahdi T, Alcalay D, Brizard A, Bois M, Millet C, Kitzis A and Tanzer J . (1996). Exp. Hematol., 24, 702–712.

  • Mora PT, Chandrasekaran K and McFarland VW . (1980). Nature, 288, 722–724.

  • Morioka K, Tone S, Mukaida M and Takano-Ohmuros H . (1998). Exp. Cell Res., 240, 206–217.

  • Peller S, Yona R, Kopilova Y, Prokocimer M, Goldfinger N, Uysal A, Karabulut HG, Tukun A, Bokesoy I, Tuncman G and Rotter V . (1998). Genes Chromosomes Cancer, 21, 2–7.

  • Polyak K, Xia Y, Zweier JL, Kinzler KW and Vogelstein B . (1997). Nature, 389, 300–305.

  • Rehberger PA, Richter KH, Schwartz D, Goldfinger N, Oskato R, Almog N, Marks F and Rotter V . (1997). Cell Growth Differ., 8, 851–860.

  • Rogel A, Poplinker M, Webb SG and Oren M . (1985). Mol. Cell Biol., 5, 2851–2855.

  • Rotter V, Schwartz D, Almon E, Goldfinger N, Kapon A, Meshorer A, Donehower LA and Levine AJ . (1993). Proc. Natl. Acad. Sci. USA, 90, 9075–9079.

  • Schmid P, Lorenz A, Hameister H and Montenarh M . (1991). Development, 113, 857–865.

  • Schwartz D, Goldfinger N, Kam Z and Rotter V . (1999). Cell Growth Differ, 10, 665–675.

  • Schwartz D, Goldfinger N and Rotter V . (1993). Oncogene, 8, 1487–1494.

  • Silva M, Grillot D, Benito A, Richard C, Nunez G and Fernandez-Luna JL . (1996). Blood, 88, 1576–1582.

  • Silva M, Richard C, Benito A, Sanz C, Olalla I and Ferandez-Luna JL . (1998). N. Engl. J. Med., 338, 564–571.

  • Wintrobe . (1999). Wintrobe's Clinical Hematology, 10th edn. Williams andQ4 Wilkins: USA.

    Google Scholar 

  • Wlodarski P, Wasik M, Ratajczak MZ, Sevignani C, Hoser G, Kawiak J, Gewirtz AM, Calabretta B and Skorski T . (1998). Blood, 91, 2998–3006.

  • Yonish-Rouach E, Resnitzky K, Lotem J, Sachs L, Kimchi A and Oren M . (1991). Nature, 352, 345–347.

  • Yuan J, Angelucci E, Lucarelli G, Alijuf M, Snyder LM, Kiefer CR, Ma L and Schrier SL . (1993). Blood, 82, 374–377.

  • Zauberman A, Lupo A and Oren M . (1995). Oncogenes, 10, 2361–2366.

  • Zermati Y, Garrido C, Amsellem S, Fishelson S, Bouscary D, Valensi F, Varet B, Solary E and Hermine O . (2001). J. Exp. Med., 193, 247–254.

  • Zeuner A, Eramo A, Peschle C and De Maria R . (1999). Cell Death, 6, 1075–1080.

Download references

Acknowledgements

The excellent technical assistance of Mrs Miri Rotschild is acknowledged. This study was supported by a grant from the Israel Cancer Association (SP) and in part by grants from the Israel–USA Binational Science Foundation (BSF) (VR), and the Kadoori Foundation VR. VR is the incumbent of the Norman and Helen Asher Professorial Chair in Cancer Research at the Weizmann Institute.

Author information

Authors and Affiliations

  1. Department of Hematology, Assaf Harofeh Medical Center, Zerifin, 70300, Israel

    Shoshana Peller, Naomi Rahimi-Levene & Rivka Yona

  2. Department of Obstetrics and Gynecology, Assaf Harofeh Medical Center, Zerifin, 70300, Israel

    Jenny Frenkel & Dan J Sherman

  3. Department of Immunology, Weizmann Institute of Science, Rehovot, Israel

    Tsvee Lapidot & Joy Kahn

  4. Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel

    Lior Nissim, Naomi Goldfinger & Varda Rotter

Authors
  1. Shoshana Peller
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jenny Frenkel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tsvee Lapidot
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Joy Kahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Naomi Rahimi-Levene
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rivka Yona
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lior Nissim
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Naomi Goldfinger
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Dan J Sherman
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Varda Rotter
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shoshana Peller.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Peller, S., Frenkel, J., Lapidot, T. et al. The onset of p53-dependent apoptosis plays a role in terminal differentiation of human normoblasts. Oncogene 22, 4648–4655 (2003). https://doi.org/10.1038/sj.onc.1206541

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1206541

Keywords

This article is cited by

Search

Advanced search

Quick links