Oncogenic Regulators and Substrates of the Anaphase Promoting Complex/cyclosome Are Frequently Overexpressed in Malignant Tumors

Overview

Journal Am J Pathol

Publisher Elsevier

Specialty Pathology

Date 2007 Apr 26

PMID 17456782

Citations 62

Authors

Norman L Lehman

Rob Tibshirani

Jerry Y Hsu

Yasodha Natkunam

Brent T Harris

Robert B West

Marilyn A Masek

Kelli Montgomery

Matt van de Rijn

Peter K Jackson

Affiliations

Soon will be listed here.

Abstract

The fidelity of cell division is dependent on the accumulation and ordered destruction of critical protein regulators. By triggering the appropriately timed, ubiquitin-dependent proteolysis of the mitotic regulatory proteins securin, cyclin B, aurora A kinase, and polo-like kinase 1, the anaphase promoting complex/cyclosome (APC/C) ubiquitin ligase plays an essential role in maintaining genomic stability. Misexpression of these APC/C substrates, individually, has been implicated in genomic instability and cancer. However, no comprehensive survey of the extent of their misregulation in tumors has been performed. Here, we analyzed more than 1600 benign and malignant tumors by immunohistochemical staining of tissue microarrays and found frequent overexpression of securin, polo-like kinase 1, aurora A, and Skp2 in malignant tumors. Positive and negative APC/C regulators, Cdh1 and Emi1, respectively, were also more strongly expressed in malignant versus benign tumors. Clustering and statistical analysis supports the finding that malignant tumors generally show broad misregulation of mitotic APC/C substrates not seen in benign tumors, suggesting that a "mitotic profile" in tumors may result from misregulation of the APC/C destruction pathway. This profile of misregulated mitotic APC/C substrates and regulators in malignant tumors suggests that analysis of this pathway may be diagnostically useful and represent a potentially important therapeutic target.

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References

Tanaka T, Kimura M, Matsunaga K, Fukada D, Mori H, Okano Y . Centrosomal kinase AIK1 is overexpressed in invasive ductal carcinoma of the breast. Cancer Res. 1999; 59(9):2041-4. View

Miller J, Summers M, Hansen D, Nachury M, Lehman N, Loktev A . Emi1 stably binds and inhibits the anaphase-promoting complex/cyclosome as a pseudosubstrate inhibitor. Genes Dev. 2006; 20(17):2410-20. PMC: 1560415. DOI: 10.1101/gad.1454006. View

Sherr C, Roberts J . CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev. 1999; 13(12):1501-12. DOI: 10.1101/gad.13.12.1501. View

Zou H, McGarry T, Bernal T, Kirschner M . Identification of a vertebrate sister-chromatid separation inhibitor involved in transformation and tumorigenesis. Science. 1999; 285(5426):418-22. DOI: 10.1126/science.285.5426.418. View

Orford K, Orford C, Byers S . Exogenous expression of beta-catenin regulates contact inhibition, anchorage-independent growth, anoikis, and radiation-induced cell cycle arrest. J Cell Biol. 1999; 146(4):855-68. PMC: 2156133. DOI: 10.1083/jcb.146.4.855. View

Spruck C, Won K, Reed S . Deregulated cyclin E induces chromosome instability. Nature. 1999; 401(6750):297-300. DOI: 10.1038/45836. View

Smith M, Wilson M, Hamanaka R, Chase D, Kung H, Longo D . Malignant transformation of mammalian cells initiated by constitutive expression of the polo-like kinase. Biochem Biophys Res Commun. 1997; 234(2):397-405. DOI: 10.1006/bbrc.1997.6633. View

Jiang J, Struhl G . Regulation of the Hedgehog and Wingless signalling pathways by the F-box/WD40-repeat protein Slimb. Nature. 1998; 391(6666):493-6. DOI: 10.1038/35154. View

Cahill D, Lengauer C, Yu J, Riggins G, WILLSON J, Markowitz S . Mutations of mitotic checkpoint genes in human cancers. Nature. 1998; 392(6673):300-3. DOI: 10.1038/32688. View

10.

Bischoff J, Anderson L, Zhu Y, Mossie K, Ng L, Souza B . A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J. 1998; 17(11):3052-65. PMC: 1170645. DOI: 10.1093/emboj/17.11.3052. View

11.

Kononen J, Bubendorf L, Kallioniemi A, Barlund M, Schraml P, Leighton S . Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med. 1998; 4(7):844-7. DOI: 10.1038/nm0798-844. View

12.

Zhou H, Kuang J, Zhong L, Kuo W, Gray J, Sahin A . Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nat Genet. 1998; 20(2):189-93. DOI: 10.1038/2496. View

13.

Lukas C, Sorensen C, Kramer E, Santoni-Rugiu E, Lindeneg C, Peters J . Accumulation of cyclin B1 requires E2F and cyclin-A-dependent rearrangement of the anaphase-promoting complex. Nature. 1999; 401(6755):815-8. DOI: 10.1038/44611. View

14.

Cahill D, Kinzler K, Vogelstein B, Lengauer C . Genetic instability and darwinian selection in tumours. Trends Cell Biol. 1999; 9(12):M57-60. View

15.

Chiaur D, Murthy S, Cenciarelli C, Parks W, Loda M, Inghirami G . Five human genes encoding F-box proteins: chromosome mapping and analysis in human tumors. Cytogenet Cell Genet. 2000; 88(3-4):255-8. DOI: 10.1159/000015532. View

16.

Sorensen C, Lukas C, Kramer E, Peters J, Bartek J, Lukas J . Nonperiodic activity of the human anaphase-promoting complex-Cdh1 ubiquitin ligase results in continuous DNA synthesis uncoupled from mitosis. Mol Cell Biol. 2000; 20(20):7613-23. PMC: 86321. DOI: 10.1128/MCB.20.20.7613-7623.2000. View

17.

Latres E, Chiarle R, Schulman B, Pavletich N, Pellicer A, Inghirami G . Role of the F-box protein Skp2 in lymphomagenesis. Proc Natl Acad Sci U S A. 2001; 98(5):2515-20. PMC: 30169. DOI: 10.1073/pnas.041475098. View

18.

Gstaiger M, Jordan R, Lim M, Catzavelos C, Mestan J, Slingerland J . Skp2 is oncogenic and overexpressed in human cancers. Proc Natl Acad Sci U S A. 2001; 98(9):5043-8. PMC: 33160. DOI: 10.1073/pnas.081474898. View

19.

Reimann J, Gardner B, Margottin-Goguet F, Jackson P . Emi1 regulates the anaphase-promoting complex by a different mechanism than Mad2 proteins. Genes Dev. 2001; 15(24):3278-85. PMC: 312853. DOI: 10.1101/gad.945701. View

20.

Ren B, Cam H, Takahashi Y, Volkert T, Terragni J, Young R . E2F integrates cell cycle progression with DNA repair, replication, and G(2)/M checkpoints. Genes Dev. 2002; 16(2):245-56. PMC: 155321. DOI: 10.1101/gad.949802. View