TACC3 depletion sensitizes to paclitaxel-induced cell death and overrides p21WAF-mediated cell cycle arrest

L. Schneider, F. Essmann, A. Kletke, P. Rio, H. Hanenberg, K. Schulze-Osthoff, B. Nürnberg, R. P. Piekorz

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Regulators of the mitotic spindle apparatus are attractive cellular targets for antitumor therapy. The centrosomal protein transforming acidic coiled coil (TACC) 3 is required for spindle assembly and proper chromosome segregation. In this study, we employed an inducible RNA interference approach to downregulate TACC3 expression. We show that TACC3 knock-down in NIH3T3 fibroblasts caused aneuploidy, but failed to overtly impair mitotic progression. TACC3 depletion rather triggered a postmitotic p53-p21WAF pathway and led to a reversible cell cycle arrest. Similar effects were induced by low concentrations of paclitaxel, a spindle poison used in antitumor therapy. Interestingly, however, and unlike in TACC3-proficient cells, paclitaxel was able to induce strong polyploidy and subsequent apoptosis in TACC3-depleted cells. Even though paclitaxel treatment was associated with the activation of the survival kinase Akt and an antiapoptotic expression of cytoplasmic p21WAF and cyclin D1, this inhibition of cell death was abrogated by depletion of TACC3. Thus, our data identify TACC3 as a potential target to overcome p21WAF- associated protection of transformed cells against paclitaxel-induced cell death.

Original languageEnglish
Pages (from-to)116-125
Number of pages10
JournalOncogene
Volume27
Issue number1
DOIs
StatePublished - Jan 3 2008

Fingerprint

Paclitaxel
Cell Cycle Checkpoints
Cell Death
Chromosome Segregation
Spindle Apparatus
Polyploidy
Cytoprotection
Poisons
Cyclin D1
Aneuploidy
RNA Interference
Phosphotransferases
Down-Regulation
Fibroblasts
Apoptosis
Therapeutics
Proteins

Keywords

  • Apoptosis
  • Mitosis
  • p21
  • p53
  • Paclitaxel
  • TACC3

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Schneider, L., Essmann, F., Kletke, A., Rio, P., Hanenberg, H., Schulze-Osthoff, K., ... Piekorz, R. P. (2008). TACC3 depletion sensitizes to paclitaxel-induced cell death and overrides p21WAF-mediated cell cycle arrest. Oncogene, 27(1), 116-125. https://doi.org/10.1038/sj.onc.1210628

TACC3 depletion sensitizes to paclitaxel-induced cell death and overrides p21WAF-mediated cell cycle arrest. / Schneider, L.; Essmann, F.; Kletke, A.; Rio, P.; Hanenberg, H.; Schulze-Osthoff, K.; Nürnberg, B.; Piekorz, R. P.

In: Oncogene, Vol. 27, No. 1, 03.01.2008, p. 116-125.

Research output: Contribution to journalArticle

Schneider, L, Essmann, F, Kletke, A, Rio, P, Hanenberg, H, Schulze-Osthoff, K, Nürnberg, B & Piekorz, RP 2008, 'TACC3 depletion sensitizes to paclitaxel-induced cell death and overrides p21WAF-mediated cell cycle arrest', Oncogene, vol. 27, no. 1, pp. 116-125. https://doi.org/10.1038/sj.onc.1210628
Schneider L, Essmann F, Kletke A, Rio P, Hanenberg H, Schulze-Osthoff K et al. TACC3 depletion sensitizes to paclitaxel-induced cell death and overrides p21WAF-mediated cell cycle arrest. Oncogene. 2008 Jan 3;27(1):116-125. https://doi.org/10.1038/sj.onc.1210628
Schneider, L. ; Essmann, F. ; Kletke, A. ; Rio, P. ; Hanenberg, H. ; Schulze-Osthoff, K. ; Nürnberg, B. ; Piekorz, R. P. / TACC3 depletion sensitizes to paclitaxel-induced cell death and overrides p21WAF-mediated cell cycle arrest. In: Oncogene. 2008 ; Vol. 27, No. 1. pp. 116-125.
@article{1a67d0d8308149f69a38c3ec4f083bf9,
title = "TACC3 depletion sensitizes to paclitaxel-induced cell death and overrides p21WAF-mediated cell cycle arrest",
abstract = "Regulators of the mitotic spindle apparatus are attractive cellular targets for antitumor therapy. The centrosomal protein transforming acidic coiled coil (TACC) 3 is required for spindle assembly and proper chromosome segregation. In this study, we employed an inducible RNA interference approach to downregulate TACC3 expression. We show that TACC3 knock-down in NIH3T3 fibroblasts caused aneuploidy, but failed to overtly impair mitotic progression. TACC3 depletion rather triggered a postmitotic p53-p21WAF pathway and led to a reversible cell cycle arrest. Similar effects were induced by low concentrations of paclitaxel, a spindle poison used in antitumor therapy. Interestingly, however, and unlike in TACC3-proficient cells, paclitaxel was able to induce strong polyploidy and subsequent apoptosis in TACC3-depleted cells. Even though paclitaxel treatment was associated with the activation of the survival kinase Akt and an antiapoptotic expression of cytoplasmic p21WAF and cyclin D1, this inhibition of cell death was abrogated by depletion of TACC3. Thus, our data identify TACC3 as a potential target to overcome p21WAF- associated protection of transformed cells against paclitaxel-induced cell death.",
keywords = "Apoptosis, Mitosis, p21, p53, Paclitaxel, TACC3",
author = "L. Schneider and F. Essmann and A. Kletke and P. Rio and H. Hanenberg and K. Schulze-Osthoff and B. N{\"u}rnberg and Piekorz, {R. P.}",
year = "2008",
month = "1",
day = "3",
doi = "10.1038/sj.onc.1210628",
language = "English",
volume = "27",
pages = "116--125",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "1",

}

TY - JOUR

T1 - TACC3 depletion sensitizes to paclitaxel-induced cell death and overrides p21WAF-mediated cell cycle arrest

AU - Schneider, L.

AU - Essmann, F.

AU - Kletke, A.

AU - Rio, P.

AU - Hanenberg, H.

AU - Schulze-Osthoff, K.

AU - Nürnberg, B.

AU - Piekorz, R. P.

PY - 2008/1/3

Y1 - 2008/1/3

N2 - Regulators of the mitotic spindle apparatus are attractive cellular targets for antitumor therapy. The centrosomal protein transforming acidic coiled coil (TACC) 3 is required for spindle assembly and proper chromosome segregation. In this study, we employed an inducible RNA interference approach to downregulate TACC3 expression. We show that TACC3 knock-down in NIH3T3 fibroblasts caused aneuploidy, but failed to overtly impair mitotic progression. TACC3 depletion rather triggered a postmitotic p53-p21WAF pathway and led to a reversible cell cycle arrest. Similar effects were induced by low concentrations of paclitaxel, a spindle poison used in antitumor therapy. Interestingly, however, and unlike in TACC3-proficient cells, paclitaxel was able to induce strong polyploidy and subsequent apoptosis in TACC3-depleted cells. Even though paclitaxel treatment was associated with the activation of the survival kinase Akt and an antiapoptotic expression of cytoplasmic p21WAF and cyclin D1, this inhibition of cell death was abrogated by depletion of TACC3. Thus, our data identify TACC3 as a potential target to overcome p21WAF- associated protection of transformed cells against paclitaxel-induced cell death.

AB - Regulators of the mitotic spindle apparatus are attractive cellular targets for antitumor therapy. The centrosomal protein transforming acidic coiled coil (TACC) 3 is required for spindle assembly and proper chromosome segregation. In this study, we employed an inducible RNA interference approach to downregulate TACC3 expression. We show that TACC3 knock-down in NIH3T3 fibroblasts caused aneuploidy, but failed to overtly impair mitotic progression. TACC3 depletion rather triggered a postmitotic p53-p21WAF pathway and led to a reversible cell cycle arrest. Similar effects were induced by low concentrations of paclitaxel, a spindle poison used in antitumor therapy. Interestingly, however, and unlike in TACC3-proficient cells, paclitaxel was able to induce strong polyploidy and subsequent apoptosis in TACC3-depleted cells. Even though paclitaxel treatment was associated with the activation of the survival kinase Akt and an antiapoptotic expression of cytoplasmic p21WAF and cyclin D1, this inhibition of cell death was abrogated by depletion of TACC3. Thus, our data identify TACC3 as a potential target to overcome p21WAF- associated protection of transformed cells against paclitaxel-induced cell death.

KW - Apoptosis

KW - Mitosis

KW - p21

KW - p53

KW - Paclitaxel

KW - TACC3

UR - http://www.scopus.com/inward/record.url?scp=37849038558&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=37849038558&partnerID=8YFLogxK

U2 - 10.1038/sj.onc.1210628

DO - 10.1038/sj.onc.1210628

M3 - Article

VL - 27

SP - 116

EP - 125

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 1

ER -