Table of Contents

Volume 5, Issue 13

  July 1, 2006

  Pages 1361 - 1471

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 Issue Catalogue (MARC XML)

EXTRA VIEWS

Open Access Article

Switching on Chromatin: Mechanistic Role of Histone H4-K16 Acetylation

Michael Shogren-Knaak and Craig L. Peterson
Pages 1361 - 1365
http://dx.doi.org/10.4161/cc.5.13.2891
Abstract | PDF

DNA in eukaryotic organisms does not exist free in cells, but instead is present as chromatin, a complex assembly of DNA, histone proteins, and chromatin-associated proteins. Chromatin exhibits a complex hierarchy of structures, but in its simplest form it is composed of long linear arrays of nucleosomes. Nucleosomes contain 147 base pairs of DNA wrapped around a histone octamer, consisting of two copies each of histones H2A, H2B, H3 and H4, where 15-38 amino terminal residues of each histone protein extends past the DNA gyres to form histone “tails” 1. Chromatin provides a versatile regulatory platform for nearly all cellular processes that involve DNA, and improper chromatin regulation results in a wide range of diseases, including various cancers and congenital defects. One major way that chromatin regulates DNA utilization is through a wide range of post-translational modification of histones, including serine and threonine phosphorylation, lysine acetylation, methylation, ubiquitination, and sumoylation, and arginine methylation 2. Histone H4 K16 acetylation is a modification that occurs on the H4 histone tail and is one of the most frequent of the known histone modifications. We have demonstrated that this mark both disrupts formation of higher-order chromatin structure and changes the functional interaction of chromatin-associated proteins 3. Our results suggest a dual mechanism by which H4 K16 acetylation can ultimately facilitate genomic functions.

Open Access Article

Repair of DNA–Protein Cross-links in Mammalian Cells

Joyce T. Reardon, Yuan Cheng and Aziz Sancar
Pages 1366 - 1370
http://dx.doi.org/10.4161/cc.5.13.2892
Abstract | PDF

DNA–protein cross-links are generated by both endogenous and exogenous DNA damaging agents, as intermediates during normal DNA metabolism, and during abortive base excision repair. Cross-links are relatively common lesions that are lethal when they block progression of DNA polymerases. DNA–protein cross-links may be broadly categorized into four groups by the DNA and protein chemistries near the cross-link and by the source of the cross-link: DNA–protein cross-links may be found (1) in nicked DNA at the 3' end of one strand (topo I), (2) in nicked DNA at the 5' end of one strand (pol beta), (3) at the 5' ends of both strands adjacent to nicks in close proximity (topo II; Spo 11), and (4) in one strand of duplex DNA (UV irradiation; bifunctional carcinogens and chemotherapeutic agents). Repair mechanisms are reasonably well-defined for groups 1 and 3, and suggested for groups 2 and 4. Our work is focused on the recognition and removal of DNA–protein cross-links in duplex DNA (group 4).

Open Access Article

From Skin Cells to Ovarian Follicles?

Paul W. Dyce and Julang Li
Pages 1371 - 1375
http://dx.doi.org/10.4161/cc.5.13.2898
Abstract | PDF

Generating oocytes from cells derived from skin in vitro may provide a valuable model for identifying factors involved in germ cell formation and oocyte differentiation. In addition, the “oocytes” produced could potentially be useful for therapeutic cloning, and thus offer new possibilities for tissue therapy. We recently reported the differentiation of cells derived from porcine fetal skin into cells resembling germ cells and oocytes. A subpopulation of these cells expressed germ cell markers and formed aggregate like oocyte-cumulus complexes that secreted ovarian steroid hormones and responded to gonadotropin stimulation. Some of these aggregates extruded large oocyte-like cells that expressed markers appropriate to oocytes. We now show further evidence of germ cell marker expression during differentiation. We have also compared the oocyte-like cells with natural oocytes for their expression levels of Oct4, growth differentiation factor-9b (GDF9b), the deleted in azoospermia -like (DAZL) gene, vasa, zona pellucida (ZP), and the meiosis marker synaptonemal complex protein 3 (SCP3), and have revealed interesting similarities and differences.

Open Access Article

γH2AX as a Checkpoint Maintenance Signal

Michael Downey and Daniel Durocher
Pages 1376 - 1381
http://dx.doi.org/10.4161/cc.5.13.2899
Abstract | PDF

A key function of the conserved signaling cascade triggered by DNA damage is to promote the arrest or pause of cell cycle progression, a phenomenon commonly termed a “checkpoint”. This response allows time for DNA repair to proceed before entering a new phase of the cell cycle. Although much is known about the initiation and propagation of this signaling pathway, much less is understood about the mechanisms that lead to its extinction. Recent work highlights a role for H2AX phosphorylation as a checkpoint maintenance factor and of its dephosphorylation as a signal for resumption of the cell cycle.

Open Access Article

A New Mechanism of Inactivation of the INK4/ARF Locus

Susana Gonzalez and Manuel Serrano
Pages 1382 - 1384
http://dx.doi.org/10.4161/cc.5.13.2901
Abstract | PDF

The INK4/ARF locus encodes three tumor suppressors, p15INK4b, p16INK4a, and ARF, and is one of the main anti-oncogenic defenses of mammalian organisms. The activity of these tumor suppressors depends mostly on the transcriptional status of the locus. Recently, we have identified a conserved DNA element with the ability to regulate the locus in a global manner. Inactivation of this element, which we have named RDINK4/ARF, results in the silencing of the entire INK4/ARF locus. Interestingly, RDINK4/ARF is both a transcriptional regulatory element and a replication origin. The replication protein Cdc6 binds to RDINK4/ARF and is able to recruit histone deacetylases that result in the heterochromatinization and repression of the INK4/ARF locus. This model has striking parallelisms with the silencing of the yeast mating-type loci. Finally, it constitutes a novel oncogenic mechanism that connects the replication machinery with the inactivation of tumor suppressors.

Open Access Article

Germ Cell Sex Determination: Piecing Together a Complex Puzzle

Matthew Wawersik
Pages 1385 - 1390
http://dx.doi.org/10.4161/cc.5.13.2905
Abstract | PDF

In many multicellular organisms, proper germ cell development is crucial for production of future generations. One critical step in this process is the decision of germ cells to develop into either sperm or eggs. Defects in germ cell sex determination can lead to infertility and germ cell tumors. However, while much is known about somatic sex determination, regulation of germ cell sex is not well understood. Recent studies with Drosophila reveal that the janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway promotes male germ cell development during early stages of gonad morphogenesis 1. Here, this and other work suggesting that the JAK/STAT pathway acts alongside a host other factors to regulate germ cell sex determination is discussed. Furthermore, recent insights into mouse germ cell sex determination are reviewed; revealing a number of correlations that suggest similar mechanisms may regulate aspects of both mouse and Drosophila germline sexual dimorphism.

Open Access Article

Regulation of mTOR by Mechanically Induced Signaling Events in Skeletal Muscle

T.A. Hornberger, K.B. Sukhija and S. Chien
Pages 1391 - 1396
http://dx.doi.org/10.4161/cc.5.13.2921
Abstract | PDF

Mechanical stimuli play a major role in the regulation of skeletal muscle mass, and the maintenance of muscle mass contributes significantly to disease prevention and the quality of life. Although a link between mechanical stimuli and the regulation of muscle mass has been recognized for decades, the mechanisms involved in converting mechanical information into the molecular events that control this process have not been defined. Nevertheless, significant advancements are being made in this field, and it has recently been established that signaling through a rapamycin-sensitive pathway is necessary for mechanically induced growth of skeletal muscle. Since rapamycin is a highly specific inhibitor of a protein kinase called the mammalian target of rapamycin (mTOR), many investigators have concluded that mTOR signaling is necessary for the mechanically induced growth of skeletal muscle. In this review, we have summarized the current knowledge regarding how mechanical stimuli activate mTOR signaling, discussed the newly discovered role of phospholipase D (PLD) and phosphatidic acid (PA) in this pathway, and considered the potential roles of PLD and PA in the mechanical regulation of skeletal muscle mass.

Open Access Article

Phenotypic Activation to Discover Biological Pathways and Kinase Substrates

Richelle Sopko, Balázs Papp, Stephen G. Oliver and Brenda J. Andrews
Pages 1397 - 1402
http://dx.doi.org/10.4161/cc.5.13.2922
Abstract | PDF

Observing the effects of gene perturbation on cells or organisms has long been a standard strategy in biological research. We developed a genome-wide gene overexpression library as a new tool for large-scale functional analysis in budding yeast. Previous large-scale genetic studies have focused on applications of the deletion mutant collection, which has arguably revolutionized the functional characterization of yeast genes. While extremely powerful, deletion mutant experiments are generally limited to the characterization of loss-of-function phenotypes. We have explored the potential for using the Synthetic Genetic Array (SGA) method, a platform for high-throughput genetic analysis, with a genome-wide “overexpression array”, in which each strain on the array overexpresses a unique yeast gene. The overexpression array enables gain-of-function phenotypes to be examined on a large scale, providing a unique insight into gene function and a novel source of reagents for the global mapping of genetic networks and functional relationships amongst genes and pathways. Understanding the molecular bases of overexpression phenotypes should also shed new light on the nature of genetic dominance.

Open Access Article

Cell-Cycle-Dependent Regulation of Telomere Binding Proteins: Roles of Polo-Like Kinase

Atsuya Nishiyama and Fuyuki Ishikawa
Pages 1403 - 1406
http://dx.doi.org/10.4161/cc.5.13.2923
Abstract | PDF

The telomere is a functional complex at chromosomal termini consisting of repetitive DNA and associated proteins, and protects the ends against degradation and fusion. Telomeric repeat binding factors TRF1 and TRF2 bind directly to double-stranded telomeric DNA. Although structurally related, TRF1 and TRF2 contribute to telomere maintenance in distinct ways: TRF1 negatively regulates telomerase-dependent telomere lengthening, whereas TRF2 plays an important role in protecting chromosomal ends. It is not known how the proteinaceous complex manages DNA metabolism such as DNA replication, which requires the recruitment of numerous trans-acting factors. We have found that Xenopus TRF1 (xTRF1) specifically associates with mitotic chromatin and dissociates from interphase replicating chromatin. In contrast, Xenopus TRF2 (xTRF2) binds to telomeric DNA throughout the cell cycle. Interestingly, telomerase activity is associated with the interphase chromatin, but not with the mitotic chromatin. These results support a model in which telomeres form a semi-open configuration that allows access of telomerase and replication machineries, yet protects the chromosomal ends in S phase. Interestingly, M phase specific telomere binding of xTRF1 requires Polo-like kinase, a key regulator of mitosis. We discuss the relevance of our studies and recent findings of other groups to indicate the possible role of Polo-like kinase in telomere regulation.

Open Access Article

Breast Cancer–Amplified Sequence 3, a Target of Metastasis-Associated Protein 1, Contributes to Tamoxifen Resistance in Premenopausal Patients with Breast Cancer

Anupama E. Gururaj, Caroline Holm, Göran Landberg and Rakesh Kumar
Pages 1407 - 1410
http://dx.doi.org/10.4161/cc.5.13.2924
Abstract | PDF

Lysine acetylation occurs in many protein targets, including core histones, transcription factors, and other proteins. Metastasis-associated protein 1 (MTA1) is implicated in the progression and metastasis of various epithelial tumors. Because MTA1 functions as a transcriptional coregulator, much of its role in cancer promoting processes are likely to involve its ability to regulate the transcription of downstream target genes that encode effector proteins. We recently showed that MTA1 could be posttranslationally modified by acetylation, which modulates its function as a coregulator molecule. We also defined a chromatin target of MTA1, namely, breast cancer–amplified sequence 3 (BCAS3), in the context of which MTA1 behaves as a transcriptional coactivator in breast cancer cells. Because the phenotypic effect of BCAS3 overexpression in tumors has not been defined, we investigated the consequence of increased expression of BCAS3 in human breast tumors. Here, we report that BCAS3 overexpression in hormone receptor–positive premenopausal breast cancer seemed to be associated with impaired responses to tamoxifen.. Our findings have implications for endocrine therapy.

Open Access Article

Polycomb Repressive Complexes Restrain the Expression of Lineage-Specific Regulators in Embryonic Stem Cells

Helle F. Jørgensen, Sara Giadrossi, Miguel Casanova, Mitsuhiro Endoh, Haruhiko Koseki, Neil Brockdorff and Amanda G. Fisher
Pages 1411 - 1414
http://dx.doi.org/10.4161/cc.5.13.2927
Abstract | PDF

Stem cells are characterised by a capacity to self renew and generate progeny capable of differentiating along several defined lineage paths. Embryonic Stem (ES) cells are derived from the inner cell mass (ICM) of early-stage embryos and can contribute to all tissues of the developing embryo. Discovering how ES cell pluripotency and lineage induction is achieved is important for understanding normal development and for successfully applying stem cell-based therapies. A series of recent studies have shown that the chromatin profile of ES cells is unusual and have revealed a critical role for the Polycomb Repressive Complexes (PRCs) in maintaining pluripotency. In human and mouse ES cells many genes that encode transcription factors that are required for lineage specification bind PRC2 and carry bivalent (or opposing) histone signatures, being enriched for conventional indicators of active chromatin such as acetylated H3K9 and methylated H3K4, while lying within domains of repressive trimethylated H3K27. Mutant ES cells that lack H3K27 methylation inappropriately expressed these genes showing that PRC2 represses lineage-specific gene programs in ES cells. Here we discuss the implications of these new discoveries and explore the interdependence of PRC1 and PRC2 in regulating lineage-specific gene expression in ES cells.




PERSPECTIVES

Open Access Article

Immense Promises for Tiny Molecules: Uncovering miRNA Functions

Carlos le Sage and Reuven Agami
Pages 1415 - 1421
http://dx.doi.org/10.4161/cc.5.13.2890
Abstract | PDF

With the human genome fully sequenced, the need to obtain functional knowledge of many genes became apparent. Amongst them is a large set of recently discovered genes with powerful promise: the microRNA family. Accumulating data assigned functions in a wide array of biological processes to some miRNAs. Here we review the main approaches used to identify and validate miRNAs and describe ways to discover their functions. As potential effectors of many cellular pathways, mis-expression of miRNAs has been implicated in human cancer.

Open Access Article

Egad, More Forms of Gene Regulation: The gadd45a Story

Ashish Lal and Myriam Gorospe
Pages 1422 - 1425
http://dx.doi.org/10.4161/cc.5.13.2902
Abstract | PDF

Despite the historical hegemony of transcription, mounting evidence supports the importance of posttranscriptional gene regulation via processes such as mRNA splicing, localization, turnover, and translation. However, each of these steps is still largely viewed as an exclusive proposition, whereby a particular gene under given circumstances is controlled by a single specific regulatory mechanism. Our recent investigation of gadd45a expression in response to genotoxic stress illustrates a more complex scenario, wherein transcriptional changes operate in concert with mRNA turnover and translational regulation. gadd45a thus joins a handful of reported genes which are specifically expressed in response to cellular damage or mitogenic cues through the coordinated action of DNA- and RNA-binding proteins. Eliciting cellular responses that are strong, swift, and versatile, gene regulation by multiple factors acting on different levels is emerging as the norm, rather than the exception, for a growing collection of gene products which critically influence cellular homeostasis.

Open Access Article

Control of Murine Kidney Development by Sonic Hedgehog and its GLI Effectors

Paul S. Gill and Norman D. Rosenblum
Pages 1426 - 1430
http://dx.doi.org/10.4161/cc.5.13.2928
Abstract | PDF

Sonic Hedgehog (SHH) controls cell differentiation and morphogenesis in many tissues and species. The mammalian kidney is a paradigm for studying epithelial-mesenchymal interactions and growth factor signaling during embryogenesis. Here, we review our recent findings demonstrating that SHH is required for normal murine kidney development. During renal morphogenesis, SHH controls a hierarchy of genes including renal patterning genes, cell cycle modulators, and GLI family members. Our investigation of GLI protein processing and binding of GLI activators and repressor to SHH target genes provide insight into the molecular mechanisms by which SHH and its GLI family of effectors control renal embryogenesis. Further, we highlight the roles of BMP, WNT and FGF signaling during renal development and discuss possible interactions of these pathways with SHH signaling.




BRIEF REPORT

Open Access Article

Heat Shock Transcription Factor HSF1 Plays a Critical Role in Cell Migration via Maintaining MAP Kinase Signaling

Cornelia O’Callaghan-Sunol and Michael Y. Sherman
Pages 1431 - 1437
http://dx.doi.org/10.4161/cc.5.13.2915
Abstract | PDF

Upon cancer progression in mouse models of prostate cancer, the heat shock transcription factor Hsf1 becomes strongly upregulated, especially in metastases. We hypothesized that Hsf1 plays a role in cell migration, a process necessary for metastases. Using a cell culture model of migration in a scratch, we found that immortalized MEF cells derived from hsf1-/- animals were deficient in both basal and EGF-induced migration. MEF cell migration was dependent on JNK and ERK signaling, since inhibition of these pathways blocked EGF-stimulated cell migration. ERK was activated at the edge of the scratch in parental cells, and this activity was further increased after addition of EGF. Both basal and EGF-stimulated ERK activation were suppressed in hsf1-/- cells at the edge of the scratch. Furthermore, activation of ERK and JNK pathways by EGF was reduced in hsf1-/- cells. The impairment of MAP kinase signaling in hsf1-/- cells was partly due to the reduced expression of EGFR1. In addition, knockout of Hsf1 gene caused a second defect in MAP kinase signaling probably at the level of Ras. We conclude that HSF1 is necessary for MAP kinase signaling which in turn affects the EGF-induced cell migration.




REPORTS

Open Access Article

CIAP2 Inhibits Anigen Receptor Signaling by Targeting Bcl10 for Degredation

Shimin Hu, Allison Alcivar, LiKe Qu, Jun Tang and Xiaolu Yang
Pages 1438 - 1442
http://dx.doi.org/10.4161/cc.5.13.2866
Abstract | PDF

The cellular inhibitor of apoptosis 2 (cIAP2) is a RING-containing protein ubiquitin ligase. In a high percentage of mucosa-associated lymphoid tissue (MALT) lymphomas, cIAP2 is fused to MALT1/paracaspase as a result of the t(11;18)(q21;q21) translocation. The physiological function of cIAP2 in lymphocytes and how this function may be affected by the translocation are not well understood. We have shown that cIAP2 normally inhibits antigen receptor signaling by mediating the ubiquitination and degradation of Bcl10, a critical component for antigenic signaling to NF-κB. The cIAP2-MALT1 fusion protein lacks this E3 activity and is incapable of ubiquitinating Bcl10, likely causing enhanced Bcl10 expression. Furthermore, cIAP2-MALT1 and Bcl10 synergistically activate NF-κB. These results reveal a physiological function of cIAP2, identify Bcl10 upregulation as a unifying molecular mechanism for MALT lymphomas, and define the mechanism and effects of this upregulation in t(11;18)-positive MALT lymphomas.

Open Access Article

Genomic Instability in Precancerous Lesions before Inactivation of Tumor Suppressors p53 and APC in Patients

Youxin Yang, Johannes Fruehauf, Shuanglin Xiang and Chiang J. Li
Pages 1443 - 1447
http://dx.doi.org/10.4161/cc.5.13.2897
Abstract | PDF

The etiology and significance of genomic instability (GIN), a hallmark of human cancers, remains controversial. The paradigm that inactivation of tumor suppressors (e.g. p53 or adenomatous polyposis coli (APC) genes) leads to GIN is largely based on experiments in vitro and in animal models. It remains unclear whether GIN is a cause or a result of cancer, particularly in patients. Precancerous Barrett’s esophagus (BE) provides a clinical model to investigate GIN in cancer progression. We analyzed specimens from endoscopic biopsies or esophagectomies in patients with BE (10 cases), BE-associated esophageal adenocarcinoma (10 cases), or with normal gastro-esophageal junction (5 cases). Chromosomal enumeration probe Cep 7, 11, 12, 17 and 18 were detected by fluorescence in situ hybridization (FISH). Expression of p53 and APC were determined by immunohistochemistry. Increased p53 expression, a measurement of p53 mutations, was observed in BE with high grade dysplasia (HGD) and in BE-associated esophageal cancer (EC). The expression of wild type APC was decreased in BE with HGD and in advanced EC. Chromosomal abnormalities were found in all EC samples. Numeric changes of chromosome 7, 11 and 12 were observed in BE in 14%, 64% and 43% of cases, respectively. Aneusomy of chromosome 11 and 12 were found in ME and in BE without dysplasia, in the presence of normal expression pattern of p53 and APC. Our results suggest that GIN is an early event that occurs at precancerous stages prior to changes in tumor suppressor genes (p53 and APC) in BE-associated tumorigenesis in patients, suggesting that GIN may serve as a causative link between chronic inflammation and cancer.

Open Access Article

Loss of Rec8 from Chromosome Arm and Centromere Region is Required for Homologous Chromosome Separation and Sister Chromatid Separation, Respectively, in Mammalian Meiosis

Jibak Lee, Konosuke Okada, Sugako Ogushi, Takashi Miyano, Masashi Miyake and Masakane Yamashita
Pages 1448 - 1455
http://dx.doi.org/10.4161/cc.5.13.2903
Abstract | PDF

Chromosome separation in meiosis I is different from those in mitosis and meiosis II in that homologs separate from each other in the former while sisters do so in the latter. We show here that meiosis-specific cohesin subunit Rec8 in mouse oocytes shows essentially the same pattern of localization to those reported in yeasts1-3 and mammalian spermatocytes4,5; Rec8 along chromosome arm (armRec8) is lost at the metaphase I-to-anaphase I transition, although centromeric Rec8 (cenRec8) is maintained until the onset of anaphase II. Suppression of the loss of armRec8 by microinjection of anti-Rec8 antibody into the oocytes inhibits homolog separation but not the first polar body emission (cytokinesis). Similarly, the injection of anti-Rec8 antibody into metaphase II oocytes prevents sister separation in anaphase II after oocyte activation. These data demonstrate that the loss of armRec8 and cenRec8 is required for separation of homologs and sisters, respectively, but both are not required for other late mitotic events such as spindle elongation and cytokinesis in mouse oocytes. Further, we propose that loss of armRec8 (homolog separation) and cytokinesis are suppressed until anaphase I by Securin whose destruction is regulated by spindle checkpoint-proteasome pathway, and that Topoisomerase II is required for homolog separation independently from such pathway.

Open Access Article

An Extended Anaphase Signaling Pathway for Mad2p Includes Microtubule Organizing Center Proteins and Multiple Motor-dependent Transitions

Christina Mayer, Jason Filopei, Joe Batac, Lea Alford and Janet L. Paluh
Pages 1456 - 1463
http://dx.doi.org/10.4161/cc.5.13.2912
Abstract | PDF

An Extended Anaphase Signaling Pathway for Mad2p Includes Microtubule Organizing Center Proteins and Multiple Motor-dependent TransitionsSignaling pathways within the mitotic mechanism temporally orchestrate spindle assembly with chromosome capture and alignment, and then coordinate initiation of chromosome segregation with spindle breakdown and cytokinesis for reproductive success. Kinetochore localized Mad2p acts in the spindle assembly checkpoint pathway during prophase and prometaphase to monitor bipolar attachment of chromosomes to spindle microtubules as well as proper tension at kinetochores. Once established, Mad2p is not degraded, but instead transits to spindle poles preceding the metaphase/anaphase transition in human and yeast cells. Whether conserved relocalization of Mad2p to poles is a final step in the spindle assembly checkpoint pathway or whether the post-metaphase transition allows Mad2p to cooperate in anaphase events leading to mitotic exit has been unknown. We examined post-metaphase localization of Mad2p in fission yeast. Our observations indicate an extended signaling pathway for Mad2p that includes kinetochore to bipolar localization at spindle poles, then additional transitions from bipolar to unipolar to equatorial. We determined that Mad2p associates with the microtubule organizing center complex through direct binding to Alp4p and that microtubule motor proteins Kinesin-14 Pkl1 and Dynein contribute to Mad2p anaphase transitions. At anaphase B onset, bipolar to unipolar transitions of both Mad2p and the septation intitiation network (SIN) kinase Cdc7 are observed. We determined that Mad2p and Cdc7p transitions monitor different events in anaphase, but that neither are required for anaphase B initiation. Our findings indicate that altered Mad2p anaphase spindle localizations can reflect changes in spindle function during mitotic exit that could contribute to fidelity in anaphase events.

Open Access Article

Alk1 and Alk2 are Two New Cell Cycle-Regulated Haspin-Like Proteins in Budding Yeast

Alessandro Nespoli, Raffaella Vercillo, Lisa di Nola, Laura Diani, Michele Giannattasio, Paolo Plevani and Marco Muzi-Falconi
Pages 1464 - 1471
http://dx.doi.org/10.4161/cc.5.13.2914
Abstract | PDF

Haspin is a protein kinase identified in mouse and human cells, and genes coding for haspin-like proteins are present in virtually all eukaryotic genomes sequenced so far. Two haspin homologues, called Alk1 and Alk2, are present in the yeast Saccharomyces cerevisiae. Both Alk1 and Alk2 exhibit a weak auto-kinase activity in vitro, are phosphoproteins in vivo and are hyperphosphorylated in response to DNA damage. The amount and modification of the two proteins is greatly regulated during the cell cycle. In fact, Alk1 and Alk2 levels peak in mitosis and late-S/G2, respectively, and phosphorylation of both proteins is maximal in mitosis. Control of protein stability plays a major role in Alk2 regulation. The half-life of Alk2 is particularly short in G1; mutagenesis and genetic analysis indicate that its degradation is controlled by the APC pathway. Overexpression of ALK2, but not of ALK1, causes a mitotic arrest, which is correlated to the kinase activity of the protein. This finding, together with its cell cycle regulation, suggests a role for Alk2 in the control of mitosis.