Table of Contents

Volume 5, Issue 6

  March 16, 2006

  Pages 563 - 667

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 Issue Catalogue (MARC XML)

CUTTING EDGE VIEWS

Open Access Article

PAX3-FKHR Chimeric Oncoprotein: Hiding Itself from Immune Detection?

John Anderson and Nourredine Himoudi
Pages 563 - 564
http://dx.doi.org/10.4161/cc.5.6.2544
Abstract | PDF

No abstract available

Open Access Article

Elimination of Keratinocytes Atagnant in S Phase Through Epidermal Turnover Instead of In Situ Apoptosis

Frank R. de Gruijl, Leon H.F. Mullenders and Gerdine J. Stout
Pages 565 - 566
http://dx.doi.org/10.4161/cc.5.6.2562
Abstract | PDF

No abstract available.

Open Access Article

The Human Papillomavirus E7 Protein Shines a Spotlight on the pRB Family Member, p130

Ann Roman
Pages 567 - 568
http://dx.doi.org/10.4161/cc.5.6.2571
Abstract | PDF

No abstract available.

Open Access Article

From Mice to Human: The “Two-Hit Model” of Leukemogenesis

Olivier Kosmider and Françoise Moreau-Gachelin
Pages 569 - 570
http://dx.doi.org/10.4161/cc.5.6.2577
Abstract | PDF

No abstract available.

Open Access Article

Negative Feedbacks in Normal Cell Growth and Their Suppression in Tumorigenesis

W.C.G. van Staveren, V. Detours, J.E. Dumont and C. Maenhaut
Pages 571 - 572
http://dx.doi.org/10.4161/cc.5.6.2582
Abstract | PDF

No abstract available.




EXTRA VIEWS

Open Access Article

Modeling Liver Cancer Using Zebrafish: A Comparative Oncogenomics Approach

Siew Hong Lam and Zhiyuan Gong
Pages 573 - 577
http://dx.doi.org/10.4161/cc.5.6.2550
Abstract | PDF

Although the zebrafish has many attributes of a promising cancer model, one outstanding question is how similar zebrafish and human tumors are at the molecular level. To date, supporting data from histology and ‘gene-to-gene’ comparisons with human data offer limited insights. Using comparative microarray analyses, we found striking molecular similarities between zebrafish and human liver neoplasia. Our data indicate that zebrafish liver tumors possess the general molecular hallmarks of human liver cancer and some of the molecular similarities extend to the progression of liver tumors. The molecular conservation between fish and human liver tumors underscored the strong association and fundamental importance of these genes in liver neoplasia as well as their clinical potentials as diagnostic markers and/or therapeutic targets. In addition, our comparative oncogenomic work provides a general framework for comparing and validating microarray data of zebrafish model with human cancer, thus adding confidence of using the zebrafish to model human cancers. 2

Open Access Article

Common Fragile Sites Nested at the Interfaces of Early and Late-Replicating Chromosome Bands : Cis Acting Components of the G2/M Checkpoint?

MIchelle Debatisse, Eliane El Achkar and Bernard Dutrillaux
Pages 578 - 581
http://dx.doi.org/10.4161/cc.5.6.2574
Abstract | PDF

Common fragile sites (CFS) are evolutionary conserved loci where damage appears recurrently upon treatments perturbing DNA synthesis. Although long studied, the mechanisms underlying CFS fragility are still incompletely understood and CFS function is unknown. We have mapped most of them at the junction of chromosomal bands replicating at different times in S phase, indicating that specific replication programs take place at CFS. In good agreement with this finding, we obtained results suggesting that CFS remain incompletely replicated up to late G2, even in cells that went unperturbed through S phase. The recent demonstration that the function of ATR and its downstream targets are crucial to CFS stability may thereby indicate that mitotic onset is delayed until completion of their replication. Altogether, available results now suggest that CFS constitute integral “cis” components of the G2-M checkpoint.

Open Access Article

BID as a Double Agent in Cell Life and Death

Atan Gross
Pages 582 - 584
http://dx.doi.org/10.4161/cc.5.6.2575
Abstract | PDF

DNA damage leads to the activation of ATM and ATR, which in turn either cause cell cycle arrest and DNA repair or apoptosis. We have demonstrated that DNA damage leads to ATM-mediated BID phosphorylation, and that this phosphorylation regulates a novel, pro-survival function of BID important for S phase arrest. Thus, BID, a member from the core apoptotic regulatory machinery (BCL-2 family) receives direct inputs from a key regulator of the cell cycle arrest/DNA repair machinery (ATM), and therefore is an excellent candidate to coordinate genotoxic stress responses and apoptotic cell death.

Open Access Article

Cdk5: A New Player in Pain Signaling

Tej K. Pareek and Ashok B. Kulkarni
Pages 585 - 588
http://dx.doi.org/10.4161/cc.5.6.2578
Abstract | PDF

Cyclin-dependent kinase 5 (Cdk5) is predominantly active in postmitotic neurons. Despite its structural homology with other cyclin-dependent kinases, Cdk5 is apparently not involved in the cell cycle process. The monomeric form of Cdk5 is inactive and requires the association of p35 or p39 in order to perform its kinase activity. This kinase is essential for normal brain development and function, but uncontrolled activity of Cdk5 may lead to numerous neurodegenerative processes. Although Cdk5 activity has been implicated in several neuronal functions, but its precise role in the peripheral nervous system has not been determined. Recently we reported for the first time the essential role for Cdk5 in pain signaling (Pareek et al., PNAS 2006). Altered nociceptive responses to basal thermal noxious stimuli in p35 knockout (p35-/-) and p35-overexpresing transgenic mice (Tgp35) have established the important role of this gene in the nociceptive process. Here, we report that Cdk5 regulates mitogen-activated protein kinase kinase1/2 (MEK1/2) activity through a negative feedback loop during the peripheral inflammatory response. Moreover a differential nociceptive response after chronic morphine exposure in p35-/- and Tgp35 mice suggests that Cdk5 activity is important for opioid tolerance. In conclusion, our data indicate important molecular roles for Cdk5 in pain signaling and opioid tolerance, which makes it a potential target for analgesic drug development.

Open Access Article

The Long and the Short of it: Linker Histone H1 is Required for Metaphase Chromosome Compaction

Thomas J. Maresca and Rebecca Heald
Pages 589 - 591
http://dx.doi.org/10.4161/cc.5.6.2581
Abstract | PDF

Faithful distribution of the genome to daughter cells requires that replicated chromatids are compacted and resolved from one another, and that functional kinetochores assemble at their centromeres to mediate spindle interactions. A molecular and mechanistic understanding of these critical processes is far from complete. We discovered that linker histone H1, a major chromatin component, is required for longitudinal compaction of replicated sperm chromosome arms in Xenopus laevis egg extracts that recapitulate the cell cycle in vitro. Due to their elongated structure, H1-depleted chromosomes could not be aligned or segregated by the spindle despite apparently normal kinetochore assembly. Interestingly, enrichment of H1 onto chromatin required passage through interphase, when DNA replication takes place. Here we show that interphase-dependent loading is also a feature of kinetochore components including Ndc80. Thus, linker histone H1 contributes to chromosome condensation in vertebrates, and important molecular determinants of mitotic chromosome and kinetochore structure and function are established during interphase.

Open Access Article

Revealing Hidden Relationships Among Yeast Genes Involved in Chromosome Segregation Using Systematic Synthetic Lethal and Synthetic Dosage Lethal Screens

Kristin Baetz, Vivien Measday and Brenda Andrews
Pages 592 - 595
http://dx.doi.org/10.4161/cc.5.6.2583
Abstract | PDF

The vast accumulation of knowledge from genome sequencing projects and studies with model organisms has presented a remarkable challenge to biologists: to understand the functions of thousands of highly conserved genes and how they work together to regulate fundamental cellular processes. This challenge is compounded by the inescapable reality that most genes are ‘buffered’ by other genes that contribute to the same biological processes, limiting the impact of phenotypic studies with single mutants. In budding yeast, functional genomic methods have been developed for the systematic application of established genetic techniques. In particular, the Synthetic Genetic Array (SGA) method allows genome-wide synthetic lethal (SL) and synthetic dosage lethal (SDL) screens thus enabling an unbiased survey of genetic interactions. We have used genes encoding components of the yeast kinetochore as a biological testbed for assaying the utility of SGA-based SL and SDL screens for revealing new pathways and genes involved in chromosome segregation. We identified 211 nonessential deletion mutants that were unable to tolerate either overexpression or loss of function of kinetochore genes. Our study uncovered a wealth of relationships between gene products that functionally interact with the kinetochore, and also highlighted the value of performing genome-wide screens with both hypomorphic and hypermorphic alleles of query genes. Here, we will highlight our recent kinetochore SGA genomic screens, in the broader context of applying complementary genetic screening approaches in the systematic exploration of biological pathways or functional complexes.

Open Access Article

P19INK4D and Cell Death

Luz E. Tavera-Mendoza, Tian-Tian Wang and John H. White
Pages 596 - 598
http://dx.doi.org/10.4161/cc.5.6.2585
Abstract | PDF

INK4 proteins are members of a family of cyclin-dependent kinase (CDK) inhibitors that function in G1 to block the activity of CDKs 4 and 6. While they share clear structural similarities, numerous studies have shown that INK4 proteins differ in their expression patterns during development and in the adult, and have differing roles in tumor suppression. A recent study from our laboratory showed that expression of the gene encoding p19INK4D is induced by the hormonal form of vitamin D3 and by retinoids, both of which signal through related nuclear receptor transcription factors. Although vitamin D3 and retinoids have distinct developmental and physiological functions, both regulate the cell cycle and have been shown to have chemopreventive effects in a range of studies. Induction of p19INK4D expression contributed to cell cycle arrest by both ligands. However, knockdown of p19INK4D rendered cells sensitive to autophagic cell death, a remarkable phenotype given the hyperproliferative responses to loss of other INK4 proteins. We discuss the relevance of our studies and recent findings of others to the cell death observed in p19INK4D-deficient animals and to a possible role for p19INK4D induction in chemoprevention.

Open Access Article

From Kinases to Cancer: Leakiness, Loss of Autoinhibition and Leukemia

Carola Reindl and Karsten Spiekermann
Pages 599 - 602
http://dx.doi.org/10.4161/cc.5.6.2586
Abstract | PDF

The class III receptor tyrosine kinase (RTK) ´Fms-like tyrosine kinase 3´ (FLT3) plays a key role in early hematopoesis. In acute myeloid leukemia (AML) two classes of activating FLT3 mutations are known: internal tandem duplications (FLT3-ITD) in the juxtamembrane domain and point mutations in the tyrosine kinase domain (FLT3-TKD). Recently, a third class of activating mutations was discovered, single point mutations in the juxtamembrane domain (FLT3-JM-PM). Since the crystal structure of the inactive conformation of FLT3 has recently been resolved the role of the juxtamembran (JM) domain, serving as a key autoinhibitory element regulating kinase activity, was elucidated. Mutations in the JM domain seem to perturb the autoinhibitory activity of the JM domain thereby inducing autonomous activation of the kinase. These findings have important clinical implications. Routine screenings for mutations in FLT3 in leukemia diagnostics should also analyze point mutations in the JM domain of FLT3 and patients harbouring FLT3-JM-PM might benefit from experimental therapeutic approaches with FLT3 inhibitors. The identification of FLT3-JM-PM is a remarkable example how single point mutations in the structurally important JM domain can turn RTKs into oncogenes.




PERSPECTIVES

Open Access Article

Akt/PKB Signaling in Cancer: A Function in Cell Motility and Invasion

Merav Yoeli-Lerner and Alex Toker
Pages 603 - 605
http://dx.doi.org/10.4161/cc.5.6.2561
Abstract | PDF

The PI 3-K signaling pathway has been the subject of intense investigation for over a decade because it regulates a multitude of cellular processes. Deregulation of this pathway often results in human diseases such as cancer. The serine/threonine kinase Akt, a major PI 3-K target in all cells, has received considerable attention because it provides tumor cells with enhanced survival capacity. Many tumors and tumor cells display elevated Akt protein expression and activity, and many of the proteins which regulate Akt itself are also often mutated in cancer. For this reason, Akt has become a viable drug target for cancer therapy. However, recent studies have shown that Akt can also function as a suppressor of tumor cell migration and invasion, phenotypes which are directly linked to metastatic tumor progression. Here we review these findings and consider the unexpected notion that Akt may function as a metastasis suppressor.

Open Access Article

Cyclin E Overexpression Reduces Infiltrative Growth in Breast Cancer: Yet Another Link Between Proliferation Control and Tumor Invasion

Pontus Berglund and Göran Landberg
Pages 606 - 609
http://dx.doi.org/10.4161/cc.5.6.2569
Abstract | PDF

Overexpression of cyclin E is strongly linked to an aggressive phenotype and poor prognosis in breast cancer. Unexpectedly, it has been shown that cyclin E overexpression decreases mobility and invasiveness of breast cancer cells. In fact, in a study of 985 breast cancers, cyclin E correlated with less infiltrative growth. This suggests a novel function for cyclin E in breast cancer tumorigenesis and a mutual control of proliferation and invasive behavior.

Open Access Article

Counting Divisions in a Human Somatic Cell Tree: How, What and Why

Darryl Shibata and Simon Tavaré
Pages 610 - 614
http://dx.doi.org/10.4161/cc.5.6.2570
Abstract | PDF

The billions of cells within an individual can be organized by genealogy into a single somatic cell tree that starts from the zygote and ends with present day cells. In theory, this tree can be reconstructed from replication errors that surreptitiously record divisions and ancestry. Such a molecular clock approach is currently impractical because somatic mutations are rare, but more feasible measurements are possible by substituting instead the 5? to 3? order of epigenetic modifications such as CpG methylation. Epigenetic somatic errors are readily detected as age-related changes in methylation, which suggests that certain adult stem cells divide frequently and “compete” for survival within niches. Potentially the genealogy of any human cell may be reconstructed without prior experimental manipulation by merely reading histories recorded in their genomes.

Open Access Article

Meisetz, A Novel Histone Tri-Methyltransferase, Regulates Meiosis-Specific Epigenesis

Katsuhiko Hayashi and Yasuhisa Matsui
Pages 615 - 620
http://dx.doi.org/10.4161/cc.5.6.2572
Abstract | PDF

Meiosis is a specialized cell division that is essential to reduce the ploidy of the genome and to generate genomic diversity in all sexually reproducing organisms. Our recent investigation revealed that the meiosis-specific histone methyltransferase Meisetz (Meiosis-induced factor containing PR/SET domain and zinc-finger motif) played an essential role on proper progression of meiotic prophase in mouse germ cell lineage. The finding also suggests that the germ cell lineage has a meiosis-specific epigenetic status that is different from that of the somatic cell lineage. This article reviews the function of Meisetz and prospects the epigenetic background allowing proper progression of meiosis in mouse germ cells.

Open Access Article

Epigenetics and Cancer: Altered Chromatin Remodeling via Snf5 Loss Leads to Aberrant Cell Cycle Regulation

Courtney G. Sansam and Charles W. M. Roberts
Pages 621 - 624
http://dx.doi.org/10.4161/cc.5.6.2579
Abstract | PDF

The term ‘epigenetics’ refers to heritable changes in gene function that occur in the absence of any change in DNA sequence. Perturbations of epigenetic gene regulation may play a critical role in the genesis of most, if not all, cancers. These alterations include changes in covalent modifications of DNA and histones as well as non-covalent changes in nucleosome positioning. Covalent epigenetic modifications have been the main focus of cancer investigation, perhaps because they are more readily assayed and understood than noncovalent modifications. Recently, evidence has emerged demonstrating that perturbation of complexes that remodel the structure of chromatin by mobilizing nucleosomes may have a key role in tumor suppression and oncogenic transformation. For example, Snf5 (Ini1/Baf47/Smarcb1), a core component of the Swi/Snf ATPase chromatin remodeling complex, is a potent tumor suppressor that is specifically inactivated in lethal childhood cancers. Notably, these cancers may serve as a paradigm for epigenetic cancers as, despite their extremely aggressive nature, the majority have an entirely normal karyotype with only microdeletions at the Snf5 locus. Recent investigations have shed light upon the mechanistic basis of Snf5 function by demonstrating that Snf5 and the Swi/Snf complex regulate the cell cycle and cooperate with p53 to prevent oncogenic transformation.

Open Access Article

Is the Loss of pRb Essential for the Mouse Skin

Sergio Ruiz, Mirentxu Santos and Jesus M. Paramio
Pages 625 - 630
http://dx.doi.org/10.4161/cc.5.6.2580
Abstract | PDF

The pRb pathway is inactivated in most, if not all, human and mouse tumors, including skin tumors. However, a relatively low frequency of Rb gene alterations is found. The embryonic lethality of pRbdeficient animals restricts the analysis of these mice to midgestation and precludes the analysis of the roles of pRb in mouse cancer models. To solve this problem, we used the Cre/LoxP technology to induce the tissue-specific deletion of pRb. In epidermis, pRb deletion leads to altered proliferation and differentiation but these alterations do not induce the development of spontaneous skin tumors. To gain insight in the possible roles of pRb in mouse skin carcinogenesis, we have performed chemical tumorigenesis experiments in mice bearing epidermal-specific inactivation of Rb gene. Unexpectedly, these mice develop fewer and smaller tumors than control animals, but showing increased malignant conversion to squamous cell carcinomas. Detailed biochemical analysis demonstrates that, in the absence of pRb, multiple pathways are activated leading to increased tumor apoptosis. In particular, we characterized the aberrant p53 activation mediated by E2F/p19ARF and other transduction pathways. This may generate a selective pressure in the tumor leading to premature p53 loss of function, which ultimately results in increased malignancy. Overall, these data highlights the role of pRb during the malignant conversion in the mouse skin carcinogenesis, and the intimate relationships between pRb and multiple tumor suppressor networks in this system.

Open Access Article

In Vitro Transformation Models: Modeling Human Cancer


Pages 631 - 635
http://dx.doi.org/10.4161/cc.5.6.2584
Abstract | PDF

The development of cancer in humans involves a complex accumulation of genetic events, as mutant alleles of proto-oncogenes, tumor-suppressor genes, and other genes that control, directly or indirectly, cell proliferation. Different combinations of these genetic alterations are observed in a given human cancer and an ever-increasing number of these genes seem to be involved in the distinct steps of neoplastic transformation. Nevertheless, recent successes in experimental models of immortalization and malignant transformation of human cells indicate that the disruption of a limited number of cellular pathways is sufficient to induce a cancerous phenotype in a wide variety of normal cells. This review will summarize recent advances in the understanding of the molecular mechanisms of malignant transformation in human cells, which suggest that a series of genetic and cellular principles may govern the formation of most, if not all, types of human cancers. Furthermore, it will give a perspective on the role of in vitro transformation models recapitulating human carcinogenesis.




REPORTS

Open Access Article

Differential Subcellular Localizations of Two Human Sgo1 Isoforms: Implications in Regulation of Sister Chromatid Cohesion and Microtubule Dynamics

Xiaoxing Wang, Yali Yang and Wei Dai
Pages 636 - 641
http://dx.doi.org/10.4161/cc.5.6.2547
Abstract | PDF

Sgo1 is an evolutionarily conserved protein that functions as a protector of centromeric cohesin during mitosis. Recent studies show that Sgo1 is kinetochore-localized and required for accurate segregation of mitotic chromosomes because depletion of Sgo1 in mammalian cells results in precocious initiation of anaphase and mis-segregation of chromosomes. Through analysis of GFP fusion proteins, we observe that two major isoforms of human Sgo1 exhibit entirely different subcellular localization patterns. The short isoform of Sgo1 (sSgo1) that lacks exon 6 does not localize to kinetochores during any stages of the cell cycle. Instead, it is enriched at mitotic spindles. On the other hand, the longer isoform of Sgo1 primarily localizes to kinetochores during G2 phase and mitotic prophase, metaphase, and anaphase. During late mitosis, Sgo1 does not appear to be associated with kinetochores. Intriguingly, the longer isoform of Sgo1 forms discrete foci during S phase, some of which are apparently in the nucleoli. However, a majority of these foci co-localize with CREST, a kinetochore antigen, indicating that Sgo1 is loaded onto kinetochores during or immediately after DNA replication. Together, our studies suggest that different isoforms of Sgo1 may play distinct roles during the cell cycle and that Sgo1 may have an interphase function as well.

Open Access Article

Identification of Novel ARF Binding Proteins by Two-Hybrid Screening

Van Tompkins, Jussara Hagen, Valerie P. Zediak and Dawn E. Quelle
Pages 642 - 647
http://dx.doi.org/10.4161/cc.5.6.2560
Abstract | PDF

The ARF tumor suppressor protects us against cancer through protein-protein interactions in partially defined p53-dependent and p53-independent pathways. We performed a two-hybrid screen using ARF as bait and present the identification of several new ARF partners that may regulate its growth inhibitory signaling. The potential physiological roles of these novel ARF binding proteins in regulating ARF signaling are discussed.

Open Access Article

Mammalian Cyclin D1/Cdk4 complexes induce cell growth in Drosophila

Sanjeev A. Datar, Mireille Galloni, Aida de la Cruz, Mark Marti, Bruce A. Edgar and Christian Frei
Pages 648 - 653
http://dx.doi.org/10.4161/cc.5.6.2573
Abstract | PDF

The Drosophila melanogaster cyclin dependent protein kinase complex CycD/Cdk4 has been shown to regulate cellular growth (accumulation of mass) as well as proliferation (cell cycle progression). In contrast, the orthologous mammalian complex has been shown to regulate cell cycle progression, but possible functions in growth control have not been addressed directly. To test whether mammalian Cyclin D1/Cdk4 complexes are capable of driving cell growth, we expressed such a complex in Drosophila. Using assays that distinguish between mass increase and cell cycle progression, we found that this complex stimulated cell growth, like its Drosophila counterpart. Furthermore, Hif-1 prolyl hydroxylase (Hph) is required for both complexes to drive growth. Our data suggest that the growth-specific function of CycD/Cdk4 is conserved from arthropods to mammals.

Open Access Article

Phosphorylation of RIα by Cyclin-Dependent Kinase CDK 2/Cyclin E Modulates the Dissociation of the RIα-RFC40 Complex

Rakhee S. Gupte, Frank Traganos, Zbigniew Darzynkiewicz and Marietta Y.W.T. Lee
Pages 654 - 661
http://dx.doi.org/10.4161/cc.5.6.2576
Abstract | PDF

We have previously demonstrated that the nuclear transport of the second subunit of the Replication Factor C complex, RFC40, by the regulatory subunit, RIα, of PKA is cell cycle specific and impairment in this transport results in G1 arrest. In this study, we have investigated whether the cyclin-dependent kinases play a role in regulating the RIα-RFC40 complex formation. In this context, we have identified RI? as a novel substrate for the G1/S-Cyclin-dependent kinase, CDK2/Cyclin E, and found that RI? is specifically phosphorylated at the serine residue. Treatment of MCF7 cells with a CDK inhibitor, olomoucine, resulted in a significant accumulation in the RI?-RFC40 complex by 3.10±0.08 fold and a parallel decrease in the RFC40-37 complex formation by 73.73±11.81%. Furthermore, in vitro phosphorylation experiments suggest that, phosphorylation of RIα by CDK2/CyclinE kinase promotes the dissociation of the RI?-RFC40 complex and that once RI? is phosphorylated it cannot complex with RFC40. Inhibition of the serine-threonine phosphatase, PP1, by Calyculin A, significantly reduced the RIα-RFC40 complex formation, substantiating the in vitro phosphorylation data. Taken together, these findings suggest that CDK2/Cyclin E may function as downstream modulator that regulates the dissociation of the RIα-RFC40 complex and subsequently the association of the RFC40-RFC37 complex.

Open Access Article

Dual Regulation of the Anaphase Promoting Complex in Human Cells by Cyclin A-Cdk2 and Cyclin A-Cdk1 Complexes

Jayashree Mitra, Greg H. Enders, Jane Azizkhan-Clifford and Kathleen L. Lengel
Pages 662 - 667
http://dx.doi.org/10.4161/cc.5.6.2604
Abstract | PDF

In mammalian somatic cells, the Anaphase Promoting Complex (APC) is inactivated during S phase by active cyclin A-Cyclin dependent kinase (Cdk) 2 complexes promoting accumulation of mitotic regulators, such as cyclin B and Polo like kinase 1 (Plk1). However, mitotic entry does not appear to be perturbed in some human cancer cells or in normal mouse cells following Cdk2 RNA interference (i) or deletion of the Cdk2 gene. These results suggest functional complementation of APC regulation by a compensatory kinase. Using Plk1 protein level as readout of APC activity, we show that APC is inactivated during S phase in human cells by both cyclin A-Cdk2 and cyclin A-Cdk1 complexes. Expression of a dominant negative mutant of Cdk2 or Cdk2 RNAi in early S phase destabilizes Plk1 as it begins to accumulate. However, this effect wanes in late S phase, where destabilization of Plk1 also requires Cdk1 RNAi. Although Cdk2 is the dominant partner of cyclin A in these settings, cyclin A also binds Cdk1. Both complexes bind the APC targeting factor Cdh1, but Cdk1 complexes are inactive in early S phase, accounting for the stronger regulation of APC function by Cdk2. These results provide further evidence that cyclin A-Cdk2 and -Cdk1 complexes display overlapping and partially redundant roles in preparing cells for mitosis, through regulation of the APC.