Anaphase-promoting complex-dependent proteolysis of cell cycle regulators and genomic instability of cancer cells

Wäsch, Ralph; Engelbert, Dirk

doi:10.1038/sj.onc.1208017

Cited by 124 publications

(118 citation statements)

References 170 publications

(201 reference statements)

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“…However, genetic and epigenetic events can occur that alter the mechanisms of cell cycle control, promoting genome instability, chromosome polyploidy and/or aneuploidy and, finally, tumor formation and progression. 68 In eukaryotes, geminin interacts with Cdt1 and regulates its activity to prevent DNA replication during inappropriate times of the cell cycle. Currently, the mechanisms by which geminin inhibits Cdt1 are not completely clear as well as the mechanisms regulating geminin transcription.…”

Section: Discussionmentioning

confidence: 99%

Role of geminin: from normal control of DNA replication to cancer formation and progression?

Montanari

Macaluso

Cittadini³

et al. 2006

Cell Death Differ

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The normal cell proliferation involves the passage through a series of finely regulated phases that are known as cell cycle checkpoints. In order to carry out a correct replication, the eukaryotic cell undergoes to a series of events ensuring that each copy of duplicated chromosome exactly segregates in each of daughter cells. 1,2 A main critical control of the cell cycle is to ensure that the DNA replication takes place and that it is followed by mitosis, once for each cell cycle. Alterations in the expression of genes that regulate the cell cycle can lead to malignant transformation and tumor progression by perturbing cell proliferation and/ or genomic stability. 3,4 The normal progression through the cell cycle is a critical step for the survival of eukaryotic cells, in which the initiation of DNA replication is under the tight control of several factors that ensure the exact duplication of chromosomes in S phase and their subsequent segregation in phase M. The strict regulation of the cell cycle combined with the presence of a licensing phase, in which the chromatin becomes licensed to be replicated, leads to the existence of a single DNA replication start site for each round of replication. 5 In this complicated network of signals regulating the cell cycle and maintaining genome integrity, the geminin protein is considered one of the main players. However, if the geminin acts as oncosuppressor gene or as a proto-oncogene is still an open question.In this article, we will report the mechanism by which geminin controls that the huge quantity of eukaryotes DNA, distributed over multiples chromosomes, is replicated once and once only for each cell cycle. Moreover, we will open and discuss an important question: what role does geminin play in cancer formation and progression? Does geminin act as an oncosuppressor, as a proto-oncogene or exhibit both roles? Geminin in the LicensingThe replication of eukaryotic genome is a complex process strictly regulated by an intricate intracellular and extracellular signaling network, which controls different phenomena such as cell proliferation, differentiation and apoptosis. 6,7 All these processes have a common function: the regulation of the initial phase of DNA replication. During this event, specific proteins sequentially assemble onto the replication origin by forming specific replicative complexes (pre-RC), which allow for the chromatin to be competent (licensed) for the next DNA replication step of the cell cycle. 8 Geminin is a 25 kDa nuclear protein that functions by inhibiting DNA replication. 9 During specific phases of the cell cycle, geminin is able to bind to Cdt1 protein and inhibits pre-RC formation. 10 In eukaryotes, the origins of replication are bound by a complex of six proteins, evolutionally well conserved among different species. 11,12 These proteins constitute the origin recognition complex (ORC) (1-6), a complex of proteins essential for the initiation of DNA replication, which was first identified in Saccharomyces cerevisiae as protein that bound t...

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Section: Discussionmentioning

confidence: 99%

Role of geminin: from normal control of DNA replication to cancer formation and progression?

Montanari

Macaluso

Cittadini³

et al. 2006

Cell Death Differ

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“…The CDK2 inhibitor p27 and cyclins B, D1, and E are the main force that drives transitions through the cell cycle by undergoing periodic ubiquitin-dependent degradation (13). p27, cyclins B, D1, and E may be classified as KNUBs as they are critical for cell cycle progression and their levels periodically oscillate due to ubiquitin-dependent degradation.…”

Section: Cycling With Ubiquitinmentioning

confidence: 99%

“…Interestingly, high levels of B-type cyclins, such as A or B1, have been found in human carcinomas of the colon and lung. Additionally, both cyclins D1 and E are frequently overexpressed in different types of human cancers, where their levels correlate with a poor quoad vitam prognosis (6,13).…”

Section: Figure 2 Examples Of Knubs and Their Regulation By Ubiquitinmentioning

confidence: 99%

“…Mutations that inactivate the APC subunits Cdc16 and Cdc23 have been described in colon carcinomas and high levels of its inhibitor Emi have been detected in several human tumors (13). Additionally, the E3 ligase h-TrCP, which targets Emi1 for proteasomal degradation, has been found to be overexpressed in several tumor cell lines and in samples of human colorectal carcinoma.…”

Section: Figure 2 Examples Of Knubs and Their Regulation By Ubiquitinmentioning

confidence: 99%

“…Additionally, Skp2 alone or in association with oncogenic Ras could induce tumor formation in two mouse models. On the other hand, Fbw7 has the features of a tumor suppressor, and indeed, inactivation mutations of the FBW7 gene have been detected in several ovarian and breast cancer cell lines expressing high levels of cyclin E. Furthermore, these mutations occur in primary endometrial carcinomas, where they may correlate with high tumor aggressiveness and scarce prognosis (6,13,15).…”

Section: Figure 2 Examples Of Knubs and Their Regulation By Ubiquitinmentioning

confidence: 99%

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Ubiquitin Hubs in Oncogenic Networks

Crosetto

Bienko

Đikić

2006

Molecular Cancer Research

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Ubiquitin is an important regulator of diverse biological functions including cell cycle progression, apoptosis, cell proliferation, and DNA damage responses. Crucial proteins involved in the control of such diverse functions are modified by ubiquitin and are frequently altered during oncogenesis. Here, we define such proteins as key-nodes regulated by ubiquitin, discuss examples of their oncogenic aberrations, and indicate how pharmacologic manipulation of such molecular hubs might improve anticancer therapy. (Mol Cancer Res 2006;4(12):899 -904)

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Protein Degradation in Cell Cycle

Shaik

Liu

Fukushima

et al. 2012

Encyclopedia of Life Sciences

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Cell cycle is a series of events that take place within a cell, leading to its division and duplication. Protein degradation through ubiquitin‐mediated proteolysis plays an important role in the cell‐cycle regulation. Most importantly, the Anaphase Promoting Complex/Cyclosome (APC/C) and the Skp1‐Cullin‐1‐F‐box complex (SCF) are the two major E3 ubiquitin ligase complexes that regulate proper cell cycle transitions by timely degrading the various key cell cycle regulators. The SCF complex controls the G1/S and the G2/M transitions by degrading Cyclin D, Cyclin E, p27, CDC6 and Wee1, whereas the APC complex facilitates the transition from metaphase to anaphase by degrading Cyclin A, Cyclin B, Securin and many other substrates. The APC complex also plays an integral role in the maintenance of chromatin metabolism, particularly in G1 and G0 via destruction of the aurora A kinase. These cell cycle transitions are tightly regulated, and defective regulation of cell cycle leads to genomic instability and ultimately cancer development. Key Concepts: Cell cycle is an essential physiological process, which generates additional number of cells when the body needs them. Cell cycle checkpoints are the built‐in control mechanisms that ensure the accuracy of cell division in eukaryotic cells. The timely destruction of various cell cycle regulators by the APC/C and the SCF complexes is necessary for proper cell cycle progression. The protein degradation pathways involve the ubiquitin‐mediated modification of substrates, which are subsequently targeted for degradation by the 26S proteasome. Misregulation of the cell cycle processes leads to abnormal cell division, chromosomal instability and subsequently cancer development.

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Anaphase-promoting complex-dependent proteolysis of cell cycle regulators and genomic instability of cancer cells

Cited by 124 publications

References 170 publications

Role of geminin: from normal control of DNA replication to cancer formation and progression?

Role of geminin: from normal control of DNA replication to cancer formation and progression?

Ubiquitin Hubs in Oncogenic Networks

Protein Degradation in Cell Cycle

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