Oncogenic regulators and substrates of the anaphase promoting complex/cyclosome are frequently overexpressed in malignant tumors.
Norman L. Lehman,Robert Tibshirani,Jerry Y. Hsu,Yasodha Natkunam,Brent T. Harris,Robert B. West,Marilyn Masek,Kelli Montgomery,Matt van de Rijn,Peter K. Jackson +9 more
TLDR
Clustering and statistical analysis supports the finding that malignant tumors generally show broad mis regulation 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.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.read more
Citations
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Deregulated proteolysis by the F-box proteins SKP2 and beta-TrCP: tipping the scales of cancer.
David Frescas,Michele Pagano +1 more
TL;DR: The functionality and biology of the F-box proteins, SKP2 (S-phase kinase-associated protein 2) and β-TrCP (β-transducin repeat-containing protein), are explored, which are emerging as important players in cancer biogenesis owing to the deregulated proteolysis of their substrates.
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Mechanisms and function of substrate recruitment by F-box proteins
TL;DR: The evolution of substrate recruitment by F-box proteins, the dysregulation of substrates in disease and potential avenues for F- box protein-directed disease therapies are focused on.
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Mitotic chromosomal instability and cancer: mouse modelling of the human disease
TL;DR: The recent literature is reviewed with an emphasis on models that recapitulate observations from human disease and how chromosome instability (CIN) arises in tumours and what consequences it has are still, however, hotly debated issues.
Journal ArticleDOI
Roles of F-box proteins in cancer
TL;DR: Additional genetic and mechanistic studies will help to define the role of each F-box protein in tumorigenesis, thereby paving the road for the rational design of F- box protein-targeted anticancer therapies.
Journal ArticleDOI
The Causes and Consequences of Polyploidy in Normal Development and Cancer
Teresa Davoli,Titia de Lange +1 more
TL;DR: Unscheduled whole-genome duplications, which take place in a substantial fraction of human tumors and have been proposed to constitute an important step in the development of cancer aneuploidy, are explored.
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