Skip to main content
SpringerLink
Log in

Effects of ionizing radiation on cell cycle progression

A review

  • Original Paper
  • Published:
Radiation and Environmental Biophysics Aims and scope Submit manuscript

Abstract

Irradiation of normal eukaryotic cells results in delayed progression through the G1, S, and G2 phases of the cell cycle. The G1 arrest is regulated by the p53 tumor suppressor gene product. Irradiation results in increased expression of p53, which in turn induces a 21 kDa protein, WAF 1/Cip 1, that inhibits cyclin CDK kinases. S-phase delay is observed after relatively high doses of radiation. This delay has both radiosensitive and radioresistant components, corresponding to inhibition of DNA replicon initiation and DNA chain elongation, respectively. The mechanism for this delay is as yet undefined, but the extent of the delay appears to be under genetic control and is sensitive to the kinase inhibitor staurosporine. A delay in G2 has been demonstrated in virtually all eukaryotic cells examined in response to irradiation. Our studies have focused on the mechanisms responsible for this delay. Cyclin B1 and p34cdc2 are cell cycle control proteins that together form a kinase complex required for passage through G2 and mitosis [22]. Control of radiation-induced G2 delay is likely therefore to involve modulation of cyclin B1/p34cdc2 activity. We have shown in HeLa cells that cyclin B1 expression is decreased in a dose-dependent manner following irradiation. This decrease is controlled at both the level of mRNA and protein accumulation. We have also shown that radiation-sensitive rat embryo fibroblast lines (REF) immortalized with v- or c-myc display a minimal G2 delay when compared to radiation resistant cells transformed with v-myc + H-ras. These REF lines respond to irradiation with a decrease in cyclin B mRNA, which parallels the extent of their respective G2 delays. The duration of the G2 delay in radiation-resistant REF can be shortened by treatment with low doses of the kinase inhibitor staurosporine. We have also been able to markedly reduce the radiation-induced G2 delay in HeLa cells using either staurosporine or caffeine. Attenuation of the G2 delay is accompanied by reversal of the radiation-induced inhibition of cyclin B mRNA accumulation. The results of these studies are consistent with the hypothesis that reduced expression of cyclin B in response to radiation is in part responsible for the G2 delay. The duration of the G2 delay may also be influenced by the activation state of the cyclin B/p34cdc2 complex.

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

Similar content being viewed by others

References

  1. Brach M, Hass R, Sherman M, Gungi M, Weichselbaum R, Kufe D (1991) Ionizing radiation induces expression and binding activity of the nuclear factor kB. J Clin Invest 88:691–695

    Google Scholar 

  2. Busse PM, Bose SK (1978) The action of caffeine on X-irradiated HeLa cells. III. Enhancement of X-ray induced killing during G2 arrest. Radiat Res 76:292–307

    Google Scholar 

  3. Ducommun B, Brambilla P, Felix M, Franza BR, Karsenti J, Draetta G (1991) cdc2 phosphorylation is required for its interaction with cyclin. EMBO J 10:3311–3319

    Google Scholar 

  4. El-Diery WS, Harper JW, O'Connor PM, Verlculescu VE, Canman C, Jackman J, Pietenpol J, Burrell M, Hill DE, Winman KG, Mercer WE, Kastan MB, Kohn KW, Elledge SJ, Kinzler KW, Vogelstein B (1994) Waf l/Cip 1 is induced in p53 mediated G1 arrest and apoptosis. Cancer Res 54:1169–1174

    PubMed  Google Scholar 

  5. Fornace AJ, Nebert DW, Hollander MC, Leethy JD, Papathanasiou J, Fargnoli N, Holbrook J (1989) Mammalian genes coordinately regulated by growth arrest signals and DNA-damaging agents. Mol Cell Biol 9:4196–4203

    Google Scholar 

  6. Girard F, Strausfeld U, Fernandez A, Lamb NJC (1991) Cyclin A is required for the onset of DNA replication in mammalian fibroblasts. Cell 67:1169–1179

    Google Scholar 

  7. Harper JW, Adami GR, Wei N, Keyomarcki K, Elledge SJ (1993) The p21 cdk-interacting protein Cip 1 is a potent inhibitor of G1 cyclin dependent kinases. Cell 75:805–816

    PubMed  Google Scholar 

  8. Hoffmann I, Clarke PR, Marcote MJ, Karsenti E, Draetta G (1993) Phosphorylation and activation of human cdc25-C by cdc2-cyclin B and its involvement in the self-amplification of MPF at mitosis. EMBO 112:53–63

    Google Scholar 

  9. Hollander M, Fornance AJ Jr (1989) Induction of fos RNA by DNA-damaging agents. Canvcer Res 49:168–192

    Google Scholar 

  10. Iliakis G, Metzher L, Muschel RJ, McKenna WG (1990) Induction and repair of DNA double strand breaks in radiation-resistant cells obtained by transformation of primary rat embryo cells with the oncogenes H-ras and V-myc. Radiat Res 50:6575–6579

    Google Scholar 

  11. Kastan MB, Onyekwere O, Sidransky D, Vogelstein B, Craig R (1991) Participation of p53 protein in the cellular/response to DNA damage. Can Res 511:6304–6311

    Google Scholar 

  12. Kobayashi H, Stewart E, Poon R, Adamczewski JP, Gannon J, Hunt T (1991) Identification of the domains in cyclin A required for binding to and activation of p34cdc2 and p32cdk2 protein kinase subunits. Mot Biol Cell 3:1279–1294

    Google Scholar 

  13. Kuerbitz SJ, Plunkett BS, Walsh WV, Kastan MB (1992) Wildtype p53 is a cell cycle checkpoint determinant following irradiation. Proc Natl Acad Sci USA 89:7491–7495

    PubMed  Google Scholar 

  14. Luca F, Shibuya EK, Dohrmann CD, Ruderman JV (1991) Both cyclin A delta 60 and B delta 97 are stable and arrest cells in M phase, but only cyclin B delta 97 turns on cyclin destruction. EMBO J 10:4311–4320

    Google Scholar 

  15. Makino F, Okada S (1975) Effects of ionizing radiation on DNA replication in cultured mammalian cells. Radiat Res 62:37–51

    Google Scholar 

  16. Markiewicz D, Flick M, Maity A, McKenna WG, Muschel RJ (1994) The effects of radiation on the expression of a newly cloned and characterized rat cyclin B mRNA. Int J Radiat Oncol Biol Phys 28:135–144

    Google Scholar 

  17. McKenna WG, Weiss MC, Endlich B, Ling CC, Bakanauskas VJ, Kelsten ML, Muschel RJ (1990) Synergistic effect of the v-myc oncogene with Hras on radioresistance. Cancer Res 50:97–102

    Google Scholar 

  18. Murray AW, Solomon MJ, Kirschner MW (1989) The role of cyclin synthesis and degradation in the control of maturation promoting factor activity. Nature 339:280–286

    PubMed  Google Scholar 

  19. Muschel RJ, Zhang HB, Iliakis G McKenna WG (1991) Cyclin B expression in HeLa cells during the G2 block induced by radiation. Can Res 51:5113–5117

    Google Scholar 

  20. Muschel RJ, Zhang HB, McKenna WG (1993) Differential effect of ionizing radiation of the expression of cyclin A and cyclin B in HeLa cells. Can Res 5:1128–1135

    Google Scholar 

  21. Nagasawa H, Little J (1983) Comparison of kinetics of X-ray induced cell killing in normal, ataxia telangectasia and hereditary retinoblastoma fibroblasts. Mutat Res 109:297–308

    Google Scholar 

  22. Norbury CA, Nurse P (1992) Animal cell cycles and their control. Annu Rev Biochem 61:441–470

    Google Scholar 

  23. O'Connor PM, Jackman J, Jondle D, Bhatia K, Magrath I (1993) Role of the p53 tumor suppressor gene in cell cycle arrest and radiosensitivity of Burkitt's lymphoma cell lines. Cancer Res 53:4776–4780

    Google Scholar 

  24. Painter RB, Robertson JS (1959) Effect of irradiation and theory and role of mitotic delay on the time course of labeling of HeLa S3 cells with tritiated thymidine. Radiat Res 11:206–217

    Google Scholar 

  25. Papathanasiou MA, Kerr NCK, Robbins JH, McBride OW, Alamo J, Barrett SF, Hickson ID, Fornace AJ (1991) Induction by ionizing radiation of the gadd45 gene in cultured human cells: lack of mediation by protein kinase C. Mot Cell Biol 11:1009–1016

    Google Scholar 

  26. Parker LL, Piwnica-Worms H (1992) Inactivation of the p34cdc2-cyclin B complex by the human WEE 1 tyrosine kinase. Science 257:1955–1957

    Google Scholar 

  27. Sherman M, Datta R, Hallalan D, Weichselbaum R, Kufe R (1990) Ionizing radiation regulates expression of the c-jun protooncogene. Proc Natl Acad Sci USA 87:5663–5666

    PubMed  Google Scholar 

  28. Terasima T, Tolmach LJ (1963) Variations in several responses of HeLa cells to X-irradiation during the division cycle. Biophys J 3:11–33

    PubMed  Google Scholar 

  29. Tsai LH, Harlow E, Meyerson M (1991) Isolation of the human cdk2 gene that encodes the cyclin A and adenovirus EIA associated p33 kinase. Nature 353:174–178

    PubMed  Google Scholar 

  30. Wang Y, Cheong N, Iliakis G (1993) Persistent inhibition of DNA synthesis in irradiated rat embryo fibroblasts expressing the oncogenes H-ras plus v-myc derives from inhibition of replicon initiation and is mitigated by staurosporine. Can Res 53:1213–1217

    Google Scholar 

  31. Watanabe I (1974) Radiation effects on DNA chain growth in mammalian cells. Radiat Res 58:541–556

    Google Scholar 

  32. Whitmore GF, Stanners CP, Till JE, Gulyas S (1961) Nucleic acid synthesis and the division cycle in X-irradiated L-strain mouse cells. Biochem Biophys Acta 47:66–77

    Google Scholar 

  33. Yamada M, Puck TT (1961) Action of radiation on mammalian cells. IV. Reversible mitotic lag in the S3 HeLa cell produced by low doses of X-rays. Proc Natl Acad Sci USA 47:1181–1191

    Google Scholar 

  34. Yu CK, Sinclair WK (1967) Mitotic delay and chromosomal aberrations induced by X-rays in synchronized Chinese hamster cells in vitro. J Natl Cancer Inst 39:619–632

    Google Scholar 

  35. Zampetti-Bosseler F, Scott D (1981) Cell death, chromosome damage and mitotic delay in normal human, ataxia telangectasia and retinoblastoma fibroblasts after X-irradiation. Int J Radiat Biol 39:547–558

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, University of Pennsylvania School of Medicine, 19104, Philadelphia, PA, USA

    Eric J. Bernhard, Amit Maity & W. Gillies McKenna

  2. Pathology and Laboratory of Medicine, University of Pennsylvania School of Medicine, 19104, Philadelphia, PA, USA

    Ruth J. Muschel

Authors
  1. Eric J. Bernhard
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amit Maity
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ruth J. Muschel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. W. Gillies McKenna
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bernhard, E.J., Maity, A., Muschel, R.J. et al. Effects of ionizing radiation on cell cycle progression. Radiat Environ Biophys 34, 79–83 (1995). https://doi.org/10.1007/BF01275210

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01275210

Keywords

Search

Navigation