본문 바로가기
KERD
논문KCI 등재

Repression of the F-box protein Skp2 is essential for actin damage-induced tetraploid G1 arrest

2

조회

0

다운로드

2

인용

0

참고문헌

키워드

주제분류화학

초록

We previously reported that p53 plays a role as a key regulator in the tetraploid G1 checkpoint, which is activated by actin damage-induced cytokinesis blockade and then prevents uncoupled DNA replication and nuclear division without cytokinesis. In this study, we investigated a role of Skp2, which targets CDK2 inhibitor p27/Kip1, in actin damage-induced tetraploid G1 arrest. Expression of Skp2 was reduced, but p27/Kip1 was increased, after actin damage-induced cytokinesis blockade. The role of Skp2 repression in tetraploid G1 arrest was investigated by analyzing the effects of ectopic expression of Skp2. After actin damage, ectopic expression of Skp2 resulted in DNA synthesis and accumulation of multinucleated cells, and ultimately, induction of apoptosis. These results suggest that Skp2 repression is important for sustaining tetraploid G1 arrest after cytokinesis blockade and is required to prevent uncoupled DNA replication and nuclear division without cytokinesis.

Abstract

We previously reported that p53 plays a role as a key regulator in the tetraploid G1 checkpoint, which is activated by actin damage-induced cytokinesis blockade and then prevents uncoupled DNA replication and nuclear division without cytokinesis. In this study, we investigated a role of Skp2, which targets CDK2 inhibitor p27/Kip1, in actin damage-induced tetraploid G1 arrest. Expression of Skp2 was reduced, but p27/Kip1 was increased, after actin damage-induced cytokinesis blockade. The role of Skp2 repression in tetraploid G1 arrest was investigated by analyzing the effects of ectopic expression of Skp2. After actin damage, ectopic expression of Skp2 resulted in DNA synthesis and accumulation of multinucleated cells, and ultimately, induction of apoptosis. These results suggest that Skp2 repression is important for sustaining tetraploid G1 arrest after cytokinesis blockade and is required to prevent uncoupled DNA replication and nuclear division without cytokinesis.

참고문헌 (24)

  1. Hartwell LH, "Checkpoints: controls that ensure the order of cell cycle events", Science, 246, pp.629~634 (1989)
  2. Kuerbitz SJ, "Wild-type p53 is a cell cycle checkpoint determinant following irradiation", Proc Natl Acad Sci U S A, 89, pp.7491~7495 (1992)
  3. Bunz F, "Requirement for p53 and p21 to sustain G2 arrest after DNA damage", Science, 282, pp.1497~1501 (1998)
  4. Lanni JS, "Characterization of the p53-dependent postmitotic checkpoint following spindle disruption", Mol Cell Biol, 18, pp.1055~1064 (1998)
  5. Khan S, "p53 and pRb prevent rereplication in response to microtubule inhibitors by mediating a reversible G1 arrest", Cancer Res, 58, pp.396~401 (1998)
  6. Di Leonardo A, "DNA rereplication in the presence of mitotic spindle inhibitors in human and mouse fibroblasts lacking either p53 or pRb function", Cancer Res, 57, pp.1013~1019 (1997)
  7. Andreassen PR, "Tetraploid state induces p53-dependent arrest of nontransformed mammalian cells in G1", Mol Biol Cell, 12, pp.1315~1328 (2001)
  8. Chae HD, "Oocyte-based screening of cytokinesis inhibitors and identification of pectenotoxin-2 that induces Bim", Bax-mediated apoptosis in p53-deficient tumors, 2005, pp.24, 4813~4819
  9. 윤언정, "p53 Prevents Immature Escaping from Cell Cycle G2 Checkpoint Arrest through Inhibiting cdk2-dependent NF-Y Phosphorylation", Cancer Research and Treatment, 38(4), pp.224~228 (2006), 대한암학회
  10. Cheng M, "The p21(Cip1) and p27(Kip1) CDK 'inhibitors' are essential activators of cyclin D-dependent kinases in murine fibroblasts", EMBO J, 18, pp.1571~1583 (1999)
  11. Carrano AC, "SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27", Nat Cell Biol, 1, pp.193~199 (1999)
  12. Frescas D, "Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer", Nat Rev Cancer, 8, pp.438~449 (2008)
  13. Traub F, "Prognostic impact of Skp2 and p27 in human breast cancer", Breast Cancer Res Treat, 99, pp.185~191 (2006)
  14. Sutterluty H, "p45SKP2 promotes p27Kip1 degradation and induces S phase in quiescent cells", Nat Cell Biol, 1, pp.207~214 (1999)
  15. Lin HK, "Skp2 targeting suppresses tumorigenesis by Arf-p53-independent cellular senescence", Nature, 464, pp.374~379 (2010)
  16. Hee-Don Chae, "p53 and DNA-dependent protein kinase catalytic subunit independently function in regulating actin damage-induced tetraploid G1 arrest", Experimental and Molecular Medicine, 44(3), pp.236~240 (2012), 생화학분자생물학회
  17. Chae H, "Deregulation of Cdk2 causes Bim-mediated apoptosis in p53-deficient tumors following actin damage", Oncogene, 27, pp.4115~4121 (2008)
  18. Chae HD, "Oocyte-based screening of cytokinesis inhibitors and identification of pectenotoxin-2 that induces Bim", Baxmediated apoptosis in p53-deficient tumors, 2005, pp.24, 4813~4819
  19. Amati B, "Kip1 meets SKP2: new links in cell-cycle control", Nat Cell Biol, 1, pp.E91~E93 (1999)
  20. Wei W, "Degradation of the SCF component Skp2 in cell-cycle phase G1 by the anaphase-promoting complex", Nature, 428, pp.194~198 (2004)
  21. Ganiatsas S, "A splice variant of Skp2 is retained in the cytoplasm and fails to direct cyclin D1 ubiquitination in the uterine cancer cell line SK-UT", Oncogene, 20, pp.3641~3650 (2001)
  22. Chae HD, "Cdk2- dependent phosphorylation of the NF-Y transcription factor is essential for the expression of the cell cycleregulatory genes and cell cycle G1", S and G2, Oncogene, pp.2004, 23[DOI]
  23. Jung MS, "Bcl-xL and E1B-19K proteins inhibit p53-induced irreversible growth arrest and senescence by preventing reactive oxygen species-dependent p38 activation", J Biol Chem, 279, pp.17765~17771 (2004)
  24. Park M, "Constitutive activation of cyclin B1-associated cdc2 kinase overrides p53-mediated G2-M arrest", Cancer Res, 60, pp.542~545 (2000)

관련 논문AI추천

이 간행물의 다른 논문 (7건)