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Control of Centrin Stability by Aurora A

By Kara B. Lukasiewicz, Tammy M. Greenwood, Vivian C. Negron, Amy K. Bruzek, Jeffrey L. Salisbury and Wilma L. Lingle

Abstract

Aurora A is an oncogenic serine/threonine kinase which can cause cell transformation and centrosome amplification when over-expressed. Human breast tumors show excess Aurora A and phospho-centrin in amplified centrosomes. Here, we show that Aurora A mediates the phosphorylation of and localizes with centrin at the centrosome, with both proteins reaching maximum abundance from prophase through metaphase, followed by their precipitous loss in late stages of mitosis. Over-expression of Aurora A results in excess phospho-centrin and centrosome amplification. In contrast, centrosome amplification is not seen in cells over-expressing Aurora A in the presence of a recombinant centrin mutant lacking the serine phosphorylation site at residue 170. Expression of a kinase dead Aurora A results in a decrease in mitotic index and abrogation of centrin phosphorylation. Finally, a recombinant centrin mutation that mimics centrin phosphorylation increases centrin's stability against APC/C-mediated proteasomal degradation. Taken together, these results suggest that the stability of centrin is regulated in part by Aurora A, and that excess phosphorylated centrin may promote centrosome amplification in cancer

Topics: Research Article
Publisher: Public Library of Science
OAI identifier: oai:pubmedcentral.nih.gov:3121746
Provided by: PubMed Central

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Citations

  1. (1998). A centrosomal function for the human Nek2 protein kinase, a member of the NIMA family of cell cycle regulators.
  2. (2002). Activation of Cdc2/cyclin B and inhibition of centrosome amplification in cells depleted of Plk1 by siRNA.
  3. (1999). Altered centrosome structure is associated with abnormal mitoses in human breast tumors.
  4. (2002). Amplification/overexpression of a mitotic kinase gene in human bladder cancer.
  5. (1989). Anaphase onset and dephosphorylation of mitotic phosphoproteins occur concomitantly.
  6. (2008). ASAP is a novel substrate of the oncogenic mitotic kinase Aurora-A: phosphorylation on Ser625 is essential to spindle formation and mitosis.
  7. (2001). Association of centrosomal kinase STK15/BTAK mRNA expression with chromosomal instability in human breast cancers.
  8. (2010). Aurora kinase A induces miR-17–92 cluster through regulation of E2F1 transcription factor. Cell Mol Life Sci.
  9. (2004). Aurora kinases link chromosome segregation and cell division to cancer susceptibility.
  10. (2004). Aurora-A abrogation of p53 DNA binding and transactivation activity by phosphorylation of serine 215.
  11. (2009). Aurora-A interacts with Cyclin B1 and enhances its stability.
  12. (2002). Aurora-A overexpression reveals tetraploidization as a major route to centrosome amplification in p532/2 cells.
  13. (2005). Aurora-A site specificity: a study with synthetic peptide substrates.
  14. (1997). Cell cycledependent expression and spindle pole localization of a novel human protein kinase, Aik, related to Aurora of Drosophila and yeast Ipl1.
  15. (2002). Centrin-2 is required for centriole duplication in mammalian cells.
  16. (2007). Centriole overduplication through the concurrent formation of multiple daughter centrioles at single maternal templates.
  17. (2002). Centrosome amplification and overexpression of aurora A are early events in rat mammary carcinogenesis.
  18. (2002). Centrosome amplification drives chromosomal instability in breast tumor development.
  19. (1998). Centrosome hypertrophy in human breast tumors: implications for genomic stability and cell polarity.
  20. (1999). Components of an SCF ubiquitin ligase localize to the centrosome and regulate the centrosome duplication cycle.
  21. (2007). Constitutive phosphorylation of aurora-a on ser51 induces its stabilization and consequent overexpression in cancer.
  22. (2009). Converging concepts of protein folding in vitro and in vivo.
  23. (2010). Coordination of centrosome homeostasis and DNA repair is intact in MCF-7 and disrupted in MDA-MB 231 breast cancer cells.
  24. (1999). Dynamic association of proteasomal machinery with the centrosome.
  25. (2004). Estrogen mediates Aurora-A overexpression, centrosome amplification, chromosomal instability, and breast cancer in female ACI rats.
  26. (2000). GFP-centrin as a marker for centriole dynamics in living cells.
  27. (1995). Identification of a complex between centrin and heat shock proteins in CSF-arrested Xenopus oocytes and dissociation of the complex following oocyte activation.
  28. (2002). Identification of phosphorylated residues that affect the activity of the mitotic kinase Aurora-A.
  29. (1996). Keeping the centrosome cycle on track. Genome stability.
  30. (2006). Mechanism limiting centrosome duplication to once per cell cycle.
  31. (1999). Mitotic regulators govern progress through steps in the centrosome duplication cycle.
  32. (1996). Most of centrin in animal cells is not centrosome-associated and centrosomal centrin is confined to the distal lumen of centrioles.
  33. (2010). Mps1 phosphorylation sites regulate the function of centrin 2 in centriole assembly.
  34. (2007). Oncogenes and tumour suppressors take on centrosomes.
  35. (2006). Overexpression of aurora kinase A in mouse mammary epithelium induces genetic instability preceding mammary tumor formation.
  36. (2002). Phosphoregulation of kinetochore-microtubule attachments by the Aurora kinase Ipl1p.
  37. (2004). Phosphorylation by aurora kinase A induces Mdm2-mediated destabilization and inhibition of p53.
  38. (2001). Phosphorylation of centrin during the cell cycle and its role in centriole separation preceding centrosome duplication.
  39. (2007). Preventing the degradation of mps1 at centrosomes is sufficient to cause centrosome reduplication in human cells.
  40. (2003). Protein folding and misfolding.
  41. (2010). Protein quality control in the cytosol and the endoplasmic reticulum: brothers in arms.
  42. (2009). Stabilization of N-Myc is a critical function of Aurora A in human neuroblastoma.
  43. (2009). SUMO-dependent regulation of centrin-2.
  44. (1999). Temporal and spatial control of cyclin B1 destruction in metaphase.
  45. (2009). The aurora kinase A regulates GSK3beta in gastric cancer cells.
  46. (1998). Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation.
  47. (1996). Vande Woude GF