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Mortalin Biology: Life, Stress and Death pp 245–255Cite as

Mortalin: A Positive Regulator of Centrosome Duplication and Amplification

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Abstract

Numeral abnormality of centrosomes (presence of more than two centrosomes) leads to mitotic defects and high frequencies of chromosome segregation errors. Centrosome amplification occurs frequently in various types of human cancers, and is believed to be a major cause of chromosomal instability. Centrosome amplification in many cases results from over-duplication (more than one duplication in a single cell cycle) caused by aberrant activities of the positive and negative regulators of centrosome duplication. Centrosome duplication is triggered by the cyclin-dependent kinase 2 (CDK2)-cyclin E kinase complex through targeting several centrosomally localized proteins, including Mps1 kinase. In contrast, p53 tumor suppressor protein suppresses centrosome duplication partly through transactivating p21 CDK inhibitor, and partly through direct regulation at centrosomes. Mortalin localizes to centrosomes, and when overexpressed, promotes centrosome duplication and induces centrosome amplification via targeting both Mps1 and p53. Here, we discuss the involvement of mortalin in the regulation of centrosome duplication and re-duplication, revealing a new and important aspect of oncogenic activity of mortalin, namely induction of numeral abnormality of centrosomes and consequent chromosome instability.

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References

  • Blair Zajdel ME, Blair GE (1988) The intracellular distribution of the transformation-associated protein p53 in adenovirus-transformed rodent cells. Oncogene 2:579–584

    PubMed  Google Scholar 

  • Brown CR, Doxsey SJ, White E, Welch WJ (1994) Both viral (adenovirus E1B) and cellular (hsp 70, p53) components interact with centrosomes. J Cell Physiol 160:47–60

    Article  PubMed  CAS  Google Scholar 

  • Carroll PE, Okuda M, Horn HF, Biddinger P, Stambrook PJ, Gleich LL, Li YQ, Fukasawa K (1998) Centrosome hyperamplification in human cancer: chromosome instability induced by p53 mutation and/or Mdm2 overexpression. Oncogene 18:1935–1944

    Article  Google Scholar 

  • Chen Z, Indjeian VB, McManus M, Wang L, Dynlacht BD (2002) CP110, a cell cycle-dependent CDK substrate, regulates centrosome duplication in human cells. Dev Cell 3:339–350

    Article  PubMed  CAS  Google Scholar 

  • D’Assoro AB, Lingle WL, Salisbury JL (2002) Centrosome amplification and the development of cancer. Oncogene 21:6146–6153

    Article  PubMed  Google Scholar 

  • Dundas SR, Lawrie LC, Rooney PH, Murray GI (2005) Mortalin is over-expressed by colorectal adenocarcinomas and correlates with poor survival. J Pathol 205:74–81

    Article  PubMed  CAS  Google Scholar 

  • Fisk HA, Winey M (2001) The mouse Mps1p-like kinase regulates centrosome duplication. Cell 106:95–104

    Article  PubMed  CAS  Google Scholar 

  • Fisk HA, Mattison CP, Winey M (2003) Human Mps1 protein kinase is required for centrosome duplication and normal mitotic progression. Proc Natl Acad Sci U S A 100:14875–14880

    Article  PubMed  CAS  Google Scholar 

  • Fukasawa K (2005) Centrosome amplification, chromosome instability and cancer development. Cancer Lett 230:6–19

    Article  PubMed  CAS  Google Scholar 

  • Fukasawa K (2007) Oncogenes and tumour suppressors take on centrosomes. Nat Rev Cancer 7:911–924

    Article  PubMed  CAS  Google Scholar 

  • Ganem NJ, Godinho SA, Pellman D (2009) A mechanism linking extra centrosomes to chromosomal instability. Nature 460:278–282

    Article  PubMed  CAS  Google Scholar 

  • Hanashiro K, Kanai M, Geng Y, Sicinski P, Fukasawa K (2008) Roles of cyclins A and E in induction of centrosome amplification in p53-compromised cells. Oncogene 27:5288–5302

    Article  PubMed  CAS  Google Scholar 

  • Harper JW (1997) Cyclin dependent kinase inhibitors. Cancer Surv 29:91–107

    PubMed  CAS  Google Scholar 

  • Hinchcliffe HE, Li C, Thompson EA, Maller JL, Sluder G (1999) Requirement of Cdk2--cyclin E activity for repeated centrosome reproduction in Xenopus egg extracts. Science 283:851–854

    Article  PubMed  CAS  Google Scholar 

  • Hsu LC, Kapali M, Deloia JA, Gallion HH (2005) Centrosome abnormalities in ovarian cancer. Int J Cancer 113:746–751

    Article  PubMed  CAS  Google Scholar 

  • Jiang F, Caraway NP, Sabichi AL, Zhang HZ, Ruitrok A, Grossman HB, Gu J, Lerner SP, Lippman S, Katz RL (2003) Centrosomal abnormality is common in and a potential biomarker for bladder cancer. Int J Cancer 106:661–665

    Article  PubMed  CAS  Google Scholar 

  • Kanai M, Ma Z, Izumi H, Kim SH, Mattison CP, Winey M, Fukasawa K (2007) Physical and functional interaction between mortalin and Mps1 kinase. Genes Cells 12:797–810

    PubMed  CAS  Google Scholar 

  • Kawamura K, Izumi H, Ma Z, Ikeda R, Moriyama M, Tanaka T, Nojima T, Levin LS, Fujikawa-Yamamoto K, Suzuki K, Fukasawa K (2004) Induction of centrosome amplification and chromosome instability in human bladder cancer cells by p53 mutation and cyclin E overexpression. Cancer Res 64:4800–4809

    Article  PubMed  CAS  Google Scholar 

  • Koutsami MK, Tsantoulis PK, Kouloukoussa M, Apostolopoulou K, Pateras IS, Spartinou Z, Drougou A, Evangelou K, Kittas C, Bartkova J, Bartek J, Gorgoulis VG (2006) Centrosome abnormalities are frequently observed in non-small-cell lung cancer and are associated with aneuploidy and cyclin E overexpression. J Pathol 209:512–521

    Article  PubMed  CAS  Google Scholar 

  • Krämer A, Schweizer S, Neben K, Giesecke C, Kalla J, Katzenberger T, Benner A, Müller-Hermelink HK, Ho AD, Ott G (2003) Centrosome aberrations as a possible mechanism for chromosomal instability in non-Hodgkin’s lymphoma. Leukemia 17:2207–2213

    Article  PubMed  Google Scholar 

  • Lacey KR, Jackson PK, Stearns T (1999) Cyclin-dependent kinase control of centrosome duplication. Proc Natl Acad Sci U S A 96:2817–2822

    Article  PubMed  CAS  Google Scholar 

  • Lingle WL, Barrett SL, Negron VC, D’Assoro AB, Boeneman K, Liu W, Whitehead CM, Reynolds C, Salisbury JL (2002) Centrosome amplification drives chromosomal instability in breast tumor development. Proc Natl Acad Sci U S A 99:1978–1983

    Article  PubMed  CAS  Google Scholar 

  • Ma Z, Izumi H, Kanai M, Kabuyama Y, Ahn NG, Fukasawa K (2006) Mortalin controls centrosome duplication via modulating centrosomal localization of p53. Oncogene 25:5377–5390

    Article  PubMed  CAS  Google Scholar 

  • Mazia D (1987) The chromosome cycle and the centrosome cycle in the mitotic cycle. Int Rev Cytology 100:49–92

    Article  CAS  Google Scholar 

  • Mikule K, Delaval B, Kaldis P, Jurcyzk A, Hergert P, Doxsey S (2007) Loss of centrosome integrity induces p38-p53-p21-dependent G1-S arrest. Nat Cell Biol 9:160–170

    Article  PubMed  CAS  Google Scholar 

  • Morris VB, Brammall J, Noble J, Reddel R (2000) p53 localizes to the centrosomes and spindles of mitotic cells in the embryonic chick epiblast, human cell lines, and a human primary culture: an immunofluorescence study. Exp Cell Res 256:122–130

    Article  PubMed  CAS  Google Scholar 

  • Nakajima T, Moriguchi M, Mitsumoto Y, Sekoguchi S, Nishikawa T, Takashima H, Watanabe T, Katagishi T, Kimura H, Okanoue T, Kagawa K (2004) Centrosome aberration accompanied with p53 mutation can induce genetic instability in hepatocellular carcinoma. Mod Pathol 17:722–727

    Article  PubMed  CAS  Google Scholar 

  • Neben K, Tews B, Wrobel G, Hahn M, Kokocinski F, Giesecke C, Krause U, Ho AD, Krämer A, Lichter P (2004) Gene expression patterns in acute myeloid leukemia correlate with centrosome aberrations and numerical chromosome changes. Oncogene 23:2379–2384

    Article  PubMed  CAS  Google Scholar 

  • Nevins JR (1992) E2F: a link between the Rb tumor suppressor protein and viral oncoproteins. Science 258:424–429

    Article  PubMed  CAS  Google Scholar 

  • Okuda M, Horn HF, Tarapore P, Tokuyama Y, Smulian AG, Chan PK, Knudsen ES, Hofmann IA, Snyder JD, Bove KE, Fukasawa K (2000) Nucleophosmin/B23 is a target of CDK2--cyclin E in centrosome duplication. Cell 103:127–140

    Article  PubMed  CAS  Google Scholar 

  • Pihan GA, Purohit A, Wallace J, Knecht H, Woda B, Quesenberry P, Doxsey SJ (1998) Centrosome defects and genetic instability in malignant tumors. Cancer Res 58:3974–3985

    PubMed  CAS  Google Scholar 

  • Pihan GA, Purohit A, Wallace J, Malhotra R, Liotta L, Doxsey SJ (2001) Centrosome defects can account for cellular and genetic changes that characterize prostate cancer progression. Cancer Res 61:2212–2219

    PubMed  CAS  Google Scholar 

  • Sancar A, Lindsey-Boltz LA, Unsal-Kacmaz K, Linn S (2004) Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu Rev Biochem 73:39–85

    Article  PubMed  CAS  Google Scholar 

  • Sato N, Mizumoto K, Nakamura M, Nakamura K, Kusumoto M, Niiyama H, Ogawa T, Tanaka M (1999) Centrosome abnormalities in pancreatic ductal carcinoma. Clin Cancer Res 5:963–970

    PubMed  CAS  Google Scholar 

  • Sherr CJ (2006) Divorcing ARF and p53: an unsettled case. Nat Rev Cancer 6:663–673

    Article  PubMed  CAS  Google Scholar 

  • Shinmura K, Bennett RA, Tarapore P, Fukasawa K (2007) Direct evidence for the role of centrosomally localized p53 in the regulation of centrosome duplication. Oncogene 26:2939–2944

    Article  PubMed  CAS  Google Scholar 

  • Tarapore P, Horn HF, Tokuyama Y, Fukasawa K (2001a) Direct regulation of the centrosome duplication cycle by the p53-p21Waf1/Cip1 pathway. Oncogene 20:3173–3184

    Article  CAS  Google Scholar 

  • Tarapore P, Tokuyama Y, Horn HF, Fukasawa K (2001b) Difference in the centrosome duplication regulatory activity among p53 ‘hot spot’ mutants: potential role of Ser 315 phosphorylation-dependent centrosome binding of p53. Oncogene 20:6851–6863

    Article  CAS  Google Scholar 

  • Tarapore P, Okuda M, Fukasawa K (2002) A mammalian in vitro centriole duplication system: evidence for involvement of CDK2/cyclin E and Nucleophosmin/B23 in centrosome duplication. Cell Cycle 1:75–81

    Article  PubMed  CAS  Google Scholar 

  • Taylor WR, Stark GR (2001) Regulation of the G2/M transition by p53. Oncogene 20:1803–1815

    Article  PubMed  CAS  Google Scholar 

  • Tritarelli A, Oricchio E, Ciciarello M, Mangiacasale R, Palena A, Lavia P, Soddu S, Cundari E (2004) p53 localization at centrosomes during mitosis and postmitotic checkpoint are ATM-dependent and require serine 15 phosphorylation. Mol Biol Cell 15:3751–3757

    Article  PubMed  CAS  Google Scholar 

  • Wadhwa R, Takano S, Robert M, Yoshida A, Nomura H, Reddel RR, Mitsui Y, Kaul SC (1998) Inactivation of tumor suppressor p53 by mot-2, a hsp70 family member. J Biol Chem 273:29586–29591

    Article  PubMed  CAS  Google Scholar 

  • Weber RG, Bridger JM, Benner A, Weisenberger D, Ehemann V, Reifenberger G, Lichter P (1998) Centrosome amplification as a possible mechanism for numerical chromosome aberrations in cerebral primitive neuroectodermal tumors with TP53 mutations. Cytogenet. Cell Genet 83:266–269

    Article  PubMed  CAS  Google Scholar 

  • Winey M, Goetsch L, Baum P, Byers B (1991) MPS1 and MPS2: novel yeast genes defining distinct steps of spindle pole body duplication. J Cell Biol 114:745–754

    Article  PubMed  CAS  Google Scholar 

  • Yi X, Luk JM, Lee NP, Peng J, Leng X, Guan XY, Lau GK, Beretta L, Fan ST (2008) Association of mortalin (HSPA9) with liver cancer metastasis and prediction for early tumor recurrence. Mol Cell Proteomics 7:315–325

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Molecular Oncology Program, H. Lee Moffitt Cancer Center & Research Institute, 33612, FL, Tampa, USA

    Masayuki Kanai & Kenji Fukasawa

Authors
  1. Masayuki Kanai
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  2. Kenji Fukasawa
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Correspondence to Kenji Fukasawa .

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Editors and Affiliations

  1. National Institute of Advanced Industria, Central 4, Higashi 1 -1-1, Tsukuba, 305 8566, Ibaraki, Japan

    Sunil C. Kaul

  2. Science & Technology (AIST), National Insitute of Advanced Industrial, Central 4, Higashi 1-1-1, Tsukuba, 305-8562, Ibaraki, Japan

    Renu Wadhwa

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Kanai, M., Fukasawa, K. (2012). Mortalin: A Positive Regulator of Centrosome Duplication and Amplification. In: Kaul, S., Wadhwa, R. (eds) Mortalin Biology: Life, Stress and Death. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-3027-4_15

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