Oncogenic regulators and substrates of the anaphase promoting complex/cyclosome are frequently overexpressed in malignant tumors.
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.
Lehman
Norman L
NL
Department of Pathology, MC5324, Stanford University, Stanford, CA, USA. nlehman@stanford.edu
Tibshirani
Rob
R
Hsu
Jerry Y
JY
Natkunam
Yasodha
Y
Harris
Brent T
BT
West
Robert B
RB
Masek
Marilyn A
MA
Montgomery
Kelli
K
van de Rijn
Matt
M
Jackson
Peter K
PK
D064173:Anaphase-Promoting Complex-Cyclosome; D015703:Antigens, CD; D064127:Aurora Kinases; D014408:Biomarkers, Tumor / Q000032:analysis*; D015820:Cadherins / Q000096:biosynthesis; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D044783:F-Box Proteins / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D034741:RNA, Small Interfering; D046888:Tissue Array Analysis; D043743:Ubiquitin-Protein Ligase Complexes / Q000096:biosynthesis*; D000097869:Polo-Like Kinase 1
D064173:Anaphase-Promoting Complex-Cyclosome; D015703:Antigens, CD; D064127:Aurora Kinases; D014408:Biomarkers, Tumor; D015820:Cadherins; D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D043743:Ubiquitin-Protein Ligase Complexes; D000097869:Polo-Like Kinase 1; C513384:CDH1 protein, human; C498960:FBXO5 protein, human