p55CDC/hCDC20 mutant induces mitotic catastrophe by inhibiting the MAD2-dependent spindle checkpoint activity in tumor cells - PubMed (original) (raw)

p55CDC/hCDC20 mutant induces mitotic catastrophe by inhibiting the MAD2-dependent spindle checkpoint activity in tumor cells

Choong-Ryoul Sihn et al. Cancer Lett. 2003.

Abstract

Nondisjunction of chromosomes results in aneuploidy in mammalian cells causing genomic instability. The spindle checkpoint, one of the surveillance systems to maintain genomic stability, prevents missegregation of chromosomes until all the kinetochores are properly attached with bipolar spindles. When this condition is not met, MAD2, a component of the spindle checkpoint complex, associates with p55CDC/hCDC20 to inhibit ubiquitination of substrates by the anaphase-promoting complex (APC). In this study, we have focused on the biological role of the MAD2-binding domain in p55CDC/hCDC20 in the maintenance of genomic stability. Based on previous studies, we constructed a truncated p55CDC/hCDC20 mutant (F2) that harbors only the MAD2-binding domain. Interestingly, we found that in the yeast two-hybrid system, the interaction of F2 and MAD2 was stronger than that of intact p55CDC/hCDC20. We also found that in the presence of the microtubule-disrupting drug, nocodazole, U2OS cells expressing p55CDC/hCDC20 mutants bypassed the mitotic arrest and showed apoptotic morphologies, whereas cells harboring vector alone arrested at metaphase. In particular, the apoptotic phenomena were dramatically enhanced in the F2-expressing cells. These mitotic catastrophes also occurred in cells treated with other microtubule disrupting agents, such as taxol and vinblastine. In addition, the mutant cells exhibited chromosomal missegregation during mitosis, even in the absence of nocodazole. Taken together, these results suggest that agents blocking the spindle checkpoint response may induce tumor cells to become more sensitive to spindle poison drugs, providing a powerful tool to improve chemotherapy.

PubMed Disclaimer

Cited by

Original CIN: reviewing roles for APC in chromosome instability.
Rusan NM, Peifer M. Rusan NM, et al. J Cell Biol. 2008 Jun 2;181(5):719-26. doi: 10.1083/jcb.200802107. J Cell Biol. 2008. PMID: 18519734 Free PMC article. Review.
Palladium(ii), platinum(ii), and silver(i) complexes with 3-acetylcoumarin benzoylhydrazone Schiff base: Synthesis, characterization, biomolecular interactions, cytotoxic activity, and computational studies.
Elsayed SA, Elnabky IM, Aboelnga MM, El-Hendawy AM. Elsayed SA, et al. RSC Adv. 2024 Jun 18;14(27):19512-19527. doi: 10.1039/d4ra02738h. eCollection 2024 Jun 12. RSC Adv. 2024. PMID: 38895519 Free PMC article.
ULK1 phosphorylates Mad1 to regulate spindle assembly checkpoint.
Yuan F, Jin X, Li D, Song Y, Zhang N, Yang X, Wang L, Zhu WG, Tian C, Zhao Y. Yuan F, et al. Nucleic Acids Res. 2019 Sep 5;47(15):8096-8110. doi: 10.1093/nar/gkz602. Nucleic Acids Res. 2019. PMID: 31291454 Free PMC article.
Up-regulation of the mitotic checkpoint component Mad1 causes chromosomal instability and resistance to microtubule poisons.
Ryan SD, Britigan EM, Zasadil LM, Witte K, Audhya A, Roopra A, Weaver BA. Ryan SD, et al. Proc Natl Acad Sci U S A. 2012 Aug 14;109(33):E2205-14. doi: 10.1073/pnas.1201911109. Epub 2012 Jul 9. Proc Natl Acad Sci U S A. 2012. PMID: 22778409 Free PMC article.
A functional analysis reveals dependence on the anaphase-promoting complex for prolonged life span in yeast.
Harkness TA, Shea KA, Legrand C, Brahmania M, Davies GF. Harkness TA, et al. Genetics. 2004 Oct;168(2):759-74. doi: 10.1534/genetics.104.027771. Genetics. 2004. PMID: 15514051 Free PMC article.

p55CDC/hCDC20 mutant induces mitotic catastrophe by inhibiting the MAD2-dependent spindle checkpoint activity in tumor cells - PubMed (original) (raw)