Table of Contents

Volume 5, Issue 24

  December 15, 2006

  Pages 2831 - 2930

View covers archive

 Issue Catalogue (MARC XML)

EXTRA VIEWS

Open Access Article

Claspin: Timing the Cell Cycle Arrest When the Genome is Damaged

Raimundo Freire, Marcel A.T.M. van Vugt, Ivan Mamely and Rene Medema
Pages 2831 - 2834
http://dx.doi.org/10.4161/cc.5.24.3559
Abstract | PDF

DNA damage checkpoints maintain genomic integrity by delaying cell cycle progression in response to genotoxic stress and stalled replication forks. One central pathway in the checkpoint response is the ATR-Chk1 pathway, in which, upon DNA damage, ATR phosphorylates and activates the effector kinase Chk1. This process depends on the adaptor protein Claspin that bridges ATR and Chk1. Once the damage is repaired, this pathway must somehow be switched off to allow the cell to continue the cell division process, an event known as checkpoint recovery. Polo-like kinase 1 (Plk1) plays a central role during checkpoint recovery. Interestingly, the Xenopus homologue of Plk1, Plx1, is able to bind and phosphorylate Claspin, releasing it from DNA and thereby contributing to Chk1 inactivation. Moreover, it was recently demonstrated that Claspin levels are controlled by proteasomal degradation, and this is regulated by Plk1. Importantly, Plk1-mediated proteosomal degradation of Claspin appears to be essential for checkpoint recovery. Here we review these recent findings and discuss the mechanisms of checkpoint regulation by Claspin.

Open Access Article

A New Role for MicroRNA Pathways: Modulation of Degeneration Induced by Pathogenic Human Disease Proteins

Julide Bilen, Nan Liu and Nancy M. Bonini
Pages 2835 - 2838
http://dx.doi.org/10.4161/cc.5.24.3579
Abstract | PDF

MicroRNAs (miRNAs) are small noncoding RNAs that regulate the expression of target transcript mRNAs. Many miRNAs have been defined, however their roles and the processes influenced by miRNA pathways are still being elucidated. A role for miRNAs in development and cancer has been described. We recently isolated the miRNA bantam (ban) in a genetic screen for modulators of pathogenicity of a human neurodegenerative disease model in Drosophila. These studies showed that upregulation of ban mitigates degeneration induced by the pathogenic polyglutamine (polyQ) protein Ataxin-3, which is mutated in the human polyglutamine disease spinocerebellar ataxia type 3 (SCA3). To address the broader role for miRNAs in neuroprotection, we also showed that loss of all miRNAs, by dicer mutation, dramatically enhances pathogenic polyQ protein toxicity in flies and in human HeLa cells. These studies suggest that miRNAs may be important for neuronal survival in the context of human neurodegenerative disease. These studies provide the foundation to define the miRNAs involved in neurodegenerative disease, and the biological pathways affected.

Open Access Article

Beta Catenin Signaling: Linking Renal Cell Carcinoma and Polycystic Kidney Disease

Benedetta Peruzzi and Donald P. Bottaro
Pages 2839 - 2841
http://dx.doi.org/10.4161/cc.5.24.3581
Abstract | PDF

Loss of von Hippel-Lindau (VHL) tumor suppressor gene function occurs in familial and most sporadic renal cell carcinoma (RCC), resulting in the aberrant expression of genes that control cell proliferation, invasion and angiogenesis. The molecular mechanisms by which VHL loss leads to tumorigenesis are not yet fully defined. The VHL gene product, pVHL, is part of an E3 ubiquitin ligase complex that targets hypoxia inducible factors for polyubiquitination and proteosomal degradation, implicating hypoxia response genes in RCC oncogenesis. VHL loss also allows robust RCC cell invasiveness and morphogenesis in response to hepatocyte growth factor (HGF), an important regulator of kidney development and renal homeostasis. Recent elucidation of the mechanism by which pVHL represses developmental HGF responses in adult kidney has identified another oncogenically relevant E3 ligase target: β-catenin. This discovery also further unifies recent insights into the molecular pathogenesis of polycystic kidney disease, where the identification of disease genes has revealed the integration of signaling pathways associated with primary cilia function and the regulation of cell growth and differentiation.




PERSPECTIVES

Open Access Article

Dynamic Regulation of Effector Protein Binding to Histone Modifications: The Biology of HP1 Switching

Holger L. Dormann, Boo Shan Tseng, C. David Allis, Hironori Funabiki and Wolfgang Fischle
Pages 2842 - 2851
http://dx.doi.org/10.4161/cc.5.24.3540
Abstract | PDF

Post-translational modifications of histone proteins, the basic building blocks around which eukaryotic DNA is organized, are crucially involved in the regulation of genome activity as they control chromatin structure and dynamics. The recruitment of specific binding proteins that recognize and interact with particular histone modifications is thought to constitute a fundamental mechanism by which histone marks mediate biological function. For instance, tri-methylation of histone H3 lysine 9 (H3K9me3) is important for recruiting heterochromatin protein 1 (HP1) to discrete regions of the genome, thereby regulating gene expression, chromatin packaging, and heterochromatin formation. Until now, little was known about the regulation of effector-histone mark interactions, and in particular, of the binding of HP1 to H3K9me3. Recently, we and others presented evidence that a "binary methylation-phosphorylation switch" mechanism controls the dynamic release of HP1 from H3K9me3 during the cell cycle: phosphorylation of histone H3 serine 10 (H3S10ph) occurs at the onset of mitosis, interferes with HP1-H3K9me3 interaction, and therefore, ejects HP1 from its binding site. Here, we discuss the biological function of HP1 release from chromatin during mitosis, consider implications why the cell controls HP1 binding by such a methylation-phosphorylation switching mechanism, and reflect on other cellular pathways where binary switching of HP1 might occur.

Open Access Article

TGFβ Activated Kinase-1: New Insights into the Diverse Roles of TAK1 in Development and Immunity

Joseph R. Delaney and Marek Mlodzik
Pages 2852 - 2855
http://dx.doi.org/10.4161/cc.5.24.3558
Abstract | PDF

A number of recent publications have examined the role of TAK1 in model systems ranging from fly to mouse. Rather than fit into a clearly defined linear molecular pathway, TAK1 seems to act in a signaling nexus that responds to a variety of upstream signals, including inflammatory molecules and developmental cues. TAK1 then influences a number of downstream processes ranging from innate immune responses to patterning and differentiation via JNK, NFκB, and TCFβ-catenin signaling. These differences in function are not simply a matter of cell type. For example, NFκB signaling in a particular cell may or may not require TAK1 depending on the nature of the activating signal. Interestingly, the multi-task functionality of TAK1 is conserved between vertebrate and invertebrate species. Studies of TAK1 in multiple experimental systems is likely to reveal more roles for this kinase and also elucidate mechanisms by which other signaling molecules fulfill diverse signaling roles. Here we provide an overview of the data concerning TAK1 from its discovery to more recent findings and provide a synthesis of the conclusions that have arisen from the multiple model systems and experimental approaches.

Open Access Article

False Moves for Survival: Error-Prone DNA Repair in Adaptive Immunity

Berit Jungnickel
Pages 2856 - 2861
http://dx.doi.org/10.4161/cc.5.24.3564
Abstract | PDF

Genetic stability and flexibility are major determinants of organismic integrity and evolution, respectively. An intricate DNA repair network protects the genome from multiple environmental challenges, but complex specialized processes may also allow enhanced mutability in critical situations. The interdependence and interference of these two systems is best exemplified in the adaptive immune system. Here, the coordinated reprogramming of DNA processing pathways allows the adaptation of the antibody response to specific infections, but in parallel increases the risk of malignant transformation of the affected B cells. The respective decisions in DNA repair pathway choice have now been linked to damage bypass processes occurring at stalled replication forks. Future research in this area may shed light on fundamental questions of both immunology and genetics, and provide translational concepts for improved cancer prognosis and therapy.

Open Access Article

Primitive, Quiescent and Difficult to Kill: The Role of Non-Proliferating Stem Cells in Chronic Myeloid Leukemia

David J. Barnes and Junio V. Melo
Pages 2862 - 2866
http://dx.doi.org/10.4161/cc.5.24.3573
Abstract | PDF

Recent studies have identified primitive, malignant stem cells which have entered the G0-phase of the cell cycle to become 'quiescent' and which are present, in small numbers, in all chronic myeloid leukaemia (CML) patients. These cells have attracted intense scrutiny because they are proving exceptionally refractory to attempts to kill them, in vitro, using imatinib mesylate, the current first-line therapy for CML, or conventional chemotherapeutic agents, such as cytosine arabinoside. This insensitivity, or resistance, to drug treatment is ominous and has important implications for the clinical management of CML, particularly with regard to relapse following an imatinib-induced remission. In this review, we consider the known properties of this cell population, including recent evidence which suggests that transcription of BCR-ABL occurs at an exceptionally high level in these cells despite them having only a single copy of the oncogene. We also discuss possible alternative, Bcr-Abl-independent, mechanisms for the insensitivity of these cells to agents which promote apoptosis, including the putative role of transporter proteins in causing abnormal drug influx or efflux.

Open Access Article

Ubiquitin Transfer from the E2 Perspective: Why is UbcH5 So Promiscuous?

Peter S. Brzovic and Rachel E. Klevit
Pages 2867 - 2873
http://dx.doi.org/10.4161/cc.5.24.3592
Abstract | PDF

Protein ubiquitination is a regulatory process that influences nearly every aspect of eukaryotic cell biology. Pathways that range from cell-cycle progression and differentiation to DNA repair to vesicle budding all rely on regulated modification of target proteins by ubiquitin. Target proteins can be tagged by a single molecule of ubiquitin or modified by ubiquitin polymers that can vary in length and linkage specificity, and these variations influence how ubiquitination signals are interpreted. Surprisingly, little is understood regarding mechanisms of protein ubiquitination and how poly-ubiquitin chains are synthesized. Simple models to explain ubiquitin transfer have dominated the literature, but recent work suggests basic assumptions as to how proteins assemble to facilitate protein ubiquitination and poly-ubiquitin chain synthesis should be re-examined. This is particularly necessary for understanding the roles played by E2 ubiquitin-conjugating enzymes, a central protein component in all ubiquitin transfer reactions. In particular, UbcH5, a canonical E2 protein that is active in a broad number of in vitro ubiquitin transfer reactions, is capable of binding ubiquitin non-covalently on a surface distinct from its active site. This unique property allows activated UbcH5~Ub complexes to self-assemble and has a profound influence on poly-ubiquitin chain synthesis.

Open Access Article

Novel Therapeutic Targets: The PERKs of Inhibiting the Integrated Stress Response

Jamie Blais and John C. Bell
Pages 2874 - 2877
http://dx.doi.org/10.4161/cc.5.24.3597
Abstract | PDF

Oxygen supports the life of all aerobic organisms and virtually every cell type is capable of sensing decreased tissue oxygenation or hypoxia. Hypoxic microenvironments are known to exist within developing solid tumors as a result of insufficient vascular delivery of oxygen, which can limit the efficient growth and spread of the malignancy. On the other hand, clinical and experimental evidence has demonstrated that reduction in tumour blood flow can diminish the efficacy of standard anticancer therapeutics including radiotherapy and chemotherapy. Indeed, low oxygenation can accelerate malignant progression and metastasis resulting in poorer prognosis irrespective of the chosen treatment regiment. We and others have shown that tumour cells cultured under hypoxic conditions and cells in hypoxic areas of tumors activate a translational control program known as the integrated stress response (ISR). One of the key master switches in the ISR is the dynamically regulated protein kinase known as PERK. Tumors that lack PERK activity are small and compromised in their ability to translate mRNAs involved in angiogenesis and tumour survival. PERK can be activated by a number of distinct endoplasmic reticulum (ER) stresses as well as hypoxia and promotes a tumor microenvironment that favors the formation of functional microvessels and ultimately tumour growth. We hypothesize that ER stresse induced by sub-lethal doses of anticancer therapeutics could actually facilitate tumour progression by activation of the ISR. We propose that inhibitors of PERK may synergize with a variety of cancer therapeutics that directly or indirectly induce the ISR.

Open Access Article

“Oncogenic Shock”: Turning an Activated Kinase against the Tumor Cell

Sreenath V. Sharma and Jeffrey Settleman
Pages 2878 - 2880
http://dx.doi.org/10.4161/cc.5.24.3598
Abstract | PDF

Accumulating evidence indicates that mutationally activated kinases are especially good targets for anti-cancer drugs. It has been suggested that this reflects a state of “oncogene addiction” of tumor cells. We recently reported experimental studies that may provide a molecular mechanism to explain such apparent dependency. We find that oncogenic kinases produce both pro-survival and pro-apoptotic signals that decay at different rates upon oncogene inactivation. Pro-survival signals are rapidly attenuated, whereas pro-apoptotic signals are relatively longer-lived. This differential signal decay creates a temporal window during which pro-apoptotic outputs from the oncogenic kinase predominate to actively promote tumor cell death upon kinase inhibition. We refer to this mechanism as “oncogenic shock”, and suggest that it has significant implications for the optimal therapeutic use of targeted kinase inhibitors.




REVIEWS

Open Access Article

Polo-Like Kinase 1: Target and Regulator of Transcriptional Control

Bernd T. Martin and Klaus Strebhardt
Pages 2881 - 2885
http://dx.doi.org/10.4161/cc.5.24.3538
Abstract | PDF

Deregulated cell cycle control is a hallmark of cancer cells. Developmental or other mitogenic stimuli activate the proliferation of normal cells in response to the requirements of growing tissues. In contrast, cancer cells liberate from proliferative restrictions exerted by anti-proliferative signals arising from the stroma and by endogenous genetic programs that correlate to the terminal differentiation of cells. The study of cyclin-dependent kinases (Cdks) and polo-like kinases (Plks) as evolutionary conserved regulators of the cell cycle has contributed significantly to our current understanding of the mechanisms that underlie the proliferation of mammalian cells. Given the importance of Plk1 for mitotic progression the temporal expression of Plk1 is crucial and has to be tightly regulated. It is known that steady-state Plk1 mRNA and protein levels are coordinately regulated during cell cycle progression, being low during interphase but high in mitosis. This review will summarize the current knowledge on how cell cycle-dependent transcriptional regulation of the Plk1 gene is achieved. While binding sites for various transcriptional activators are dispersed throughout the entire Plk1 promoter region, the cell cycle-dependent regulation of the Plk1 gene expression seems to be regulated by G₁-specific repression rather than by G₂/M-specific activation of the Plk1 transcriptional unit. The tumor suppressor gene p53 was identified as a key player in the precise restriction of Plk1 gene expression to the G₂/M phase. The activity of p53 is in turn controlled by Plk1 itself indicating the existence of an auto-regulatory mechanism involved in the cell cycle-dependent regulation of the Plk1 gene. Furthermore, transcription factors regulated by Plk1 will also be subject of discussion.

Open Access Article

Nucleotide Excision Repair Disorders and the Balance Between Cancer and Aging

Jaan-Olle Andressoo, Jan H.J. Hoeijmakers and James R. Mitchell
Pages 2886 - 2888
http://dx.doi.org/10.4161/cc.5.24.3565
Abstract | PDF

Cancer incidence increases with age and is driven by accumulation of mutations in the DNA. In many so-called premature aging disorders, cancer appears earlier and at elevated rates. These diseases are predominantly caused by genome instability and present with symptoms, including cancer, resembling “segments” of aging and are thus often referred to as “segmental progerias”. Two related segmental progerias, Cockayne syndrome (CS) and trichothiodystrophy (TTD), don’t fit this pattern. Although caused by defects in genome maintenance via the nucleotide excision DNA repair (NER) pathway and displaying severe progeroid symptoms, CS and TTD patients appear to lack any cancer predisposition. More strikingly, genetic defects in the same NER pathway, and in some cases even within the same gene, XPD, can also give rise to disorders with greatly elevated cancer rates but without progeria (xeroderma pigmentosum). In this review, we will discuss the connection between genome maintenance, aging and cancer in light of a new mouse model of XPD disease.




BRIEF REPORTS

Open Access Article

TIS11D is a Candidate Pro-Apoptotic p53 Target Gene

Roger S. Jackson II, Yong-Jig Cho and Peng Liang
Pages 2889 - 2893
http://dx.doi.org/10.4161/cc.5.24.3539
Abstract | PDF

A number of target genes for the tumor suppressor, p53, have been identified, however, the mechanisms that contribute to p53-dependent apoptosis remain to be fully elucidated. In a comprehensive screen for p53 target genes by differential display, we have identified TIS11D as a p53-inducible gene. Induction of TIS11D mRNA was confirmed by Northern Blot in response to p53 expression. Inducible expression of TIS11D resulted in inhibition of cell proliferation and apoptosis. These data suggest TIS11D as a candidate p53 target gene that may be part of the network of genes responsible for p53-dependent apoptosis.

Open Access Article

Human Cdc14A Reverses CDK1 Phosphorylation of Cdc25A on Serines 115 and 320

Verónica Esteban, María D. Vázquez-Novelle, Enrique Calvo, Avelino Bueno and Maria P. Sacristán
Pages 2894 - 2898
http://dx.doi.org/10.4161/cc.5.24.3566
Abstract | PDF

Human Cdc14A is an evolutionary conserved dual-specificity protein phosphatase that reverses the modifications effected by cyclin-dependent kinases and plays an important role in centrosome duplication and mitotic regulation. Few substrates of Cdc14A have been identified, some of them with homologues in yeast that, in turn, are substrates of the Saccharomyces cerevisiae Cdc14 homologue, a protein phosphatase essential for yeast cell viability owing its role in mitotic exit regulation. Identification of the physiological substrates of human Cdc14A is an immediate goal in order to elucidate which cellular processes it regulates. Here, we show that human Cdc14A can dephosphorylate Cdc25A in vitro. Specifically, the Cdk1/Cyclin-B1-dependent phosphate groups on Ser115 and Ser320 of Cdc25A were found to be removed by Cdc14A. Cdc25A is an important cell cycle-regulatory protein involved in several cell cycle transitions and checkpoint responses and whose function and own regulation depend on complex phosphorylation/dephosphorylation-mediated processes. Importantly, we also show that the upregulation of Cdc14A phosphatase affects Cdc25A protein levels in human cells. Our results suggest that Cdc14A may be involved in the cell cycle regulation of Cdc25A stability.

Open Access Article

p21^Waf1/Cip1 Deficiency Stimulates Centriole Overduplication

Anette Duensing, Louis Ghanem, Richard A. Steinman, Ying Liu and Stefan Duensing
Pages 2899 - 2902
http://dx.doi.org/10.4161/cc.5.24.3567
Abstract | PDF

Inactivation of the cyclin-dependent kinase (CDK) inhibitor p21Waf1/Cip1 (CDKN1; hereafter p21) has previously been implicated in the induction of numerical centrosome alterations. It is unclear, however, whether p21 deficiency deregulates the centrosome duplication cycle itself or causes an accumulation of centrosomes due to cell division failure and/or polyploidization. Using a novel marker for maternal centrioles, Cep170, we show here that knock-down of p21 protein expression in murine myeloblasts can stimulate excessive centriole numbers in the presence of only one or two mature centrioles. These results indicate that p21 deficiency can trigger a bona fide overduplication of centrioles and that aberrant centrosome numbers cannot solely be explained by polyploidization as suggested by previous studies. Our findings underscore that impaired p21 expression may function as a driving force for chromosomal instability and highlight the importance of markers for maternal centrioles such as Cep170 to elucidate the pathogenesis of numerical centriole aberrations in tumor cells.

Open Access Article

Autologous Bone Marrow Cell Therapy and Metabolic Intervention in Ischemia-Induced Angiogenesis in the Diabetic Mouse Hindlimb

Vincenzo Sica, Sharon Williams-Ignarro, Filomena de Nigris, Francesco P. D’Armiento, Lilach O. Lerman, Maria Luisa Balestrieri, Ciro Maione, Antonio Palagiano, Luigi Rossiello, Louis Ignarro and Claudio Napoli
Pages 2903 - 2908
http://dx.doi.org/10.4161/cc.5.24.3568
Abstract | PDF

Peripheral arterial disease (PAD) is a major health problem especially when associated to diabetes. Administration of autologous bone marrow cells (BMC) is emerging as a novel intervention to induce therapeutic angiogenesis in experimental ischemic limb models and in patients with PAD. Since tissue ischemia and diabetes are associated with an overwhelming generation of oxygen radicals and detrimental effects due to formation of glycosylation end-products, metabolic intervention with antioxidants and L-arginine can confer beneficial effects beyond those achieved by BMC alone. The effects of cotreatment with intravenous BMCs and metabolic vascular protection (1.0% vitamin E, 0.05% vitamin C, and 6% L-arginine) were examined in the ischemic hindlimb of diabetic and non diabetic mice. BMC therapy increased blood flow and capillary densities and Ki67 proliferative marker, and decreased interstitial fibrosis. This effect was amplified by metabolic cotreatment, an intervention inducing vascular protection, at least in part, through the nitric oxide pathway, reduction of systemic oxidative stress, and macrophage activation.

Open Access Article

γ-H2AX in Cancer Cells: A Potential Biomarker for Cancer Diagnostics, Prediction and Recurrence

Olga A. Martin and William M. Bonner
Pages 2909 - 2913
http://dx.doi.org/10.4161/cc.5.24.3569
Abstract | PDF

Current advances in cancer biology have identified major pathways involved in tumorigenesis. The association of DNA damage with premalignant stages of tumor progression, genome instability and further oncogenic transformation opens the possibility of using common DNA damage markers for early cancer detection, prediction, prognosis, therapeutics and possibly for cancer prevention. Perhaps the most sensitive DNA damage marker is γ-H2AX formation in the chromatin flanking the free DNA double-stranded ends in double-strand breaks (DSBs) and eroded telomeres, both present during oncogenic transformation. Our group and others found elevated endogenous levels of γ-H2AX in various human cancer cell lines, premalignant lesions and solid tumors. These data suggest that increased DNA damage is a general characteristic of cancer development. γ-H2AX-based assay can be applied to human biopsies, aspirates and, possibly, to mononuclear cells of the peripheral blood. We propose that detection of γ-H2AX could benefit for the early cancer screening and to ascertain the efficiency of clinical treatment involving chemo- and radiotherapeutic protocols.




REPORTS

Open Access Article

Budding Yeast DNA Damage Adaptation Mutants Exhibit Defects in Mitotic Exit

Fengzhi Jin and Yanchang Wang
Pages 2914 - 2919
http://dx.doi.org/10.4161/cc.5.24.3570
Abstract | PDF

In the presence of double strand breaks, DNA damage checkpoint halts cell cycle progression. However, cells ultimately escape the checkpoint arrest and re-enter cell cycle in the presence of irreparable DNA damage. cdc5-ad was identified as a mutant that fails to adapt to the cell cycle arrest induced by DNA damage checkpoint. In budding yeast, Cdc5 protein kinase is a component of both MEN and FEAR pathways that are required for mitotic exit. It remains unclear whether the adaptation defect of cdc5-ad mutant cells is related to the function of Cdc5 in mitotic exit. Here we present evidence indicating that cdc5-ad mutant cells exhibit defects in mitotic exit. cdc5-ad mutant cells are sensitive to high dosage of Amn1, a negative regulator of MEN. It also shows synthetic growth defects with mutants in MEN pathway. Moreover, mutants in FEAR pathway exhibit defects in DNA damage adaptation. Thus, we conclude that the compromised mitotic exit pathway contributes to DNA damage adaptation defects in cdc5-ad mutant cells.

Open Access Article

Characterization of 14-3-3sigma Dimerization Determinants: Requirement of Homodimerization for Inhibition of Cell Proliferation

Berlinda Verdoodt, Anne Benzinger, Grzegorz M. Popowicz, Tad A. Holak and Heiko Hermeking
Pages 2920 - 2926
http://dx.doi.org/10.4161/cc.5.24.3571
Abstract | PDF

The seven highly conserved 14-3-3 proteins expressed in mammalian cells form a complex pattern of homo- and hetero-dimers, which is poorly characterized. Among the 14-3-3 proteins 14-3-3sigma is unique as it has tumor suppressive properties. Expression of 14-3-3sigma is induced by DNA damage in a p53-dependent manner and mediates a cell cycle arrest. Here we show that the 14-3-3sigma protein exclusively forms homodimers when it is ectopically expressed at high levels, whereas ectopic 14-3-3zeta formed heterodimers with the 5 other 14-3-3 isoforms. The x-ray structure of 14-3-3sigmarevealed 5 residues (Ser⁵, Glu²⁰, Phe²⁵, Q⁵⁵, Glu⁸⁰) as candidate determinants of dimerization specificity. Here we converted these amino-acids to residues present in 14-3-3zeta at the analogous positions. Thereby, Ser⁵, Glu²⁰ and Glu⁸⁰ were identified as key residues responsible for the selective homodimerization of 14-3-3sigma. Conversion of all 5 candidate residues was sufficient to switch the dimerization pattern of 14-3-3sigma to a pattern which is very similar to that of 14-3-3zeta. In contrast to wildtype 14-3-3sigma this 14-3-3sigma variant and 14-3-3zeta were unable to mediate inhibition of cell proliferation. Therefore, homodimerization by 14-3-3sigma is required for its unique functions among the 7 mammalian 14-3-3 proteins. As inactivation of 14-3-3sigma sensitizes to DNA-damaging drugs, substances designed to interfere with 14-3-3sigma dimerization may be used to inactivate 14-3-3sigma function for cancer therapeutic purposes.




LETTER TO THE EDITOR

Open Access Article

Eukaryotic Domain of Unknown Function DUF738 Belongs to Gcn5-related N-acetyltransferase Superfamily

Kamil Steczkiewicz, Lisa Kinch, Nick V. Grishin, Leszek Rychlewski and Krzysztof Ginalski
Pages 2927 - 2930
http://dx.doi.org/10.4161/cc.5.24.3572
Abstract | PDF

No Abstract available at this time.