G2 delay induced by nitrogen mustard in human cells affects cyclin A/cdk2 and cyclin B1/cdc2-kinase complexes differently - PubMed

Affiliations

• PMID: 8463339

Free article

Comparative Study

G2 delay induced by nitrogen mustard in human cells affects cyclin A/cdk2 and cyclin B1/cdc2-kinase complexes differently

P M O'Connor et al. J Biol Chem. 1993.

Free article

Abstract

We investigated the temporal regulation of cyclin A- and B1-dependent kinases in human lymphoma cells treated with nitrogen mustard (HN2) and pentoxifylline, to determine whether the activity of these complexes correlated with cell cycle arrest induced by DNA damage. Cells were synchronized in G1/S, treated with HN2, and then postincubated with pentoxifylline. HN2-induced a protracted delay in G2 phase. This delay correlated with suppression of cyclin B1- and cdc2-kinase activities, and stabilization of hyperphosphorylated-cdc2 in the presence of similar cyclin B1 levels to those found in mitosis. HN2 had no discernible effect on the S phase activity of cyclin A- or cdk2-immune complexes. Entry of control cells into mitosis correlated with destruction of cyclin A, disappearance of cyclin A-bound cdk2 and decreased cdk2 kinase activity. G2 delay induced by HN2 was associated with stabilization of cyclin A, increased abundance of cyclin A-bound cdk2, and increased cdk2 activity. Cyclin A was also associated with cdc2, which, contrary to complexes containing cdk2, were only activated upon entry into mitosis. Pentoxifylline abrogated cell cycle arrest induced by aphidicolin and HN2 in human lymphoma cells. Pentoxifylline also reverted the activity of cyclin A- and B1-kinases in HN2-treated cells to approximately that observed in controls. Our findings suggest that delayed entry into mitosis following DNA damage correlates with suppression of cyclin B1/cdc2 and cyclin A/cdc2 complexes, while maintaining cyclin A/cdc2 complexes in an active state. Furthermore, we found that pentoxifylline disrupts the signal transduction pathway that regulates these complexes when damaged DNA is present, resulting in abrogation of cell cycle arrest.

Similar articles

• Characterization of the in vitro reconstituted cyclin A or B1-dependent cdk2 and cdc2 kinase activities.

  Pan ZQ, Amin A, Hurwitz J. Pan ZQ, et al. J Biol Chem. 1993 Sep 25;268(27):20443-51. J Biol Chem. 1993. PMID: 8397207

• Loss of p53 induces M-phase retardation following G2 DNA damage checkpoint abrogation.

  Minemoto Y, Uchida S, Ohtsubo M, Shimura M, Sasagawa T, Hirata M, Nakagama H, Ishizaka Y, Yamashita K. Minemoto Y, et al. Arch Biochem Biophys. 2003 Apr 1;412(1):13-9. doi: 10.1016/s0003-9861(03)00010-9. Arch Biochem Biophys. 2003. PMID: 12646262

• Reconstitution of cyclin-dependent cdc2 and cdk2 kinase activities in vitro.

  Pan ZQ, Hurwitz J. Pan ZQ, et al. J Biol Chem. 1993 Sep 25;268(27):20433-42. J Biol Chem. 1993. PMID: 8397206

• [The characterization of human cdc2 kinase and CDK2].

  Yasuda H, Kamijo M, Ohba Y. Yasuda H, et al. Yakugaku Zasshi. 1993 Dec;113(12):829-46. doi: 10.1248/yakushi1947.113.12_829. Yakugaku Zasshi. 1993. PMID: 8301538 Review. Japanese.

• Advances in synthesis and biological evaluation of CDK2 inhibitors for cancer therapy.

  Patel DA, Patel SS, Patel HD. Patel DA, et al. Bioorg Chem. 2024 Feb;143:107045. doi: 10.1016/j.bioorg.2023.107045. Epub 2023 Dec 21. Bioorg Chem. 2024. PMID: 38147786 Review.

Cited by

• Expression of a novel non-coding mitochondrial RNA in human proliferating cells.

  Villegas J, Burzio V, Villota C, Landerer E, Martinez R, Santander M, Martinez R, Pinto R, Vera MI, Boccardo E, Villa LL, Burzio LO. Villegas J, et al. Nucleic Acids Res. 2007;35(21):7336-47. doi: 10.1093/nar/gkm863. Epub 2007 Oct 25. Nucleic Acids Res. 2007. PMID: 17962305 Free PMC article.

• Role of the cdc25C phosphatase in G2 arrest induced by nitrogen mustard.

  O'Connor PM, Ferris DK, Hoffmann I, Jackman J, Draetta G, Kohn KW. O'Connor PM, et al. Proc Natl Acad Sci U S A. 1994 Sep 27;91(20):9480-4. doi: 10.1073/pnas.91.20.9480. Proc Natl Acad Sci U S A. 1994. PMID: 7937793 Free PMC article.

• Hybrid inhibitors of DNA and HDACs remarkably enhance cytotoxicity in leukaemia cells.

  Song Y, Park SY, Wu Z, Liu KH, Seo YH. Song Y, et al. J Enzyme Inhib Med Chem. 2020 Dec;35(1):1069-1079. doi: 10.1080/14756366.2020.1754812. J Enzyme Inhib Med Chem. 2020. PMID: 32314611 Free PMC article.

• Constitutive expression of B-myb can bypass p53-induced Waf1/Cip1-mediated G1 arrest.

  Lin D, Fiscella M, O'Connor PM, Jackman J, Chen M, Luo LL, Sala A, Travali S, Appella E, Mercer WE. Lin D, et al. Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):10079-83. doi: 10.1073/pnas.91.21.10079. Proc Natl Acad Sci U S A. 1994. PMID: 7937841 Free PMC article.

• Cell cycle perturbations and apoptosis induced by isohomohalichondrin B (IHB), a natural marine compound.

  Bergamaschi D, Ronzoni S, Taverna S, Faretta M, De Feudis P, Faircloth G, Jimeno J, Erba E, D'Incalci M. Bergamaschi D, et al. Br J Cancer. 1999 Jan;79(2):267-77. doi: 10.1038/sj.bjc.6690044. Br J Cancer. 1999. PMID: 9888468 Free PMC article.

Publication types

MeSH terms

Substances

LinkOut - more resources

• Full Text Sources

  • Elsevier Science

• Other Literature Sources

  • The Lens - Patent Citations Database

• Miscellaneous

  • NCI CPTAC Assay Portal