14 results on '"Flaminia Talos"'
Search Results
2. ECMarker: Interpretable machine learning model identifies gene expression biomarkers predicting clinical outcomes and reveals molecular mechanisms of human disease in early stages
- Author
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Flaminia Talos, Nam D. Nguyen, Ting Jin, and Daifeng Wang
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Statistics and Probability ,Lung Neoplasms ,AcademicSubjects/SCI01060 ,Computer science ,Gene regulatory network ,Gene Expression ,Feature selection ,Genomics ,Disease ,Biology ,Machine learning ,computer.software_genre ,Biochemistry ,Machine Learning ,03 medical and health sciences ,symbols.namesake ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,Gene expression ,medicine ,Humans ,Lung cancer ,Molecular Biology ,Gene ,030304 developmental biology ,Interpretability ,0303 health sciences ,Artificial neural network ,business.industry ,Cancer ,medicine.disease ,Original Papers ,Computer Science Applications ,Computational Mathematics ,Computational Theory and Mathematics ,030220 oncology & carcinogenesis ,Boltzmann constant ,symbols ,Biomarker (medicine) ,Erlotinib ,Artificial intelligence ,business ,computer ,Biomarkers ,medicine.drug - Abstract
Motivation Gene expression and regulation, a key molecular mechanism driving human disease development, remains elusive, especially at early stages. Integrating the increasing amount of population-level genomic data and understanding gene regulatory mechanisms in disease development are still challenging. Machine learning has emerged to solve this, but many machine learning methods were typically limited to building an accurate prediction model as a ‘black box’, barely providing biological and clinical interpretability from the box. Results To address these challenges, we developed an interpretable and scalable machine learning model, ECMarker, to predict gene expression biomarkers for disease phenotypes and simultaneously reveal underlying regulatory mechanisms. Particularly, ECMarker is built on the integration of semi- and discriminative-restricted Boltzmann machines, a neural network model for classification allowing lateral connections at the input gene layer. This interpretable model is scalable without needing any prior feature selection and enables directly modeling and prioritizing genes and revealing potential gene networks (from lateral connections) for the phenotypes. With application to the gene expression data of non-small-cell lung cancer patients, we found that ECMarker not only achieved a relatively high accuracy for predicting cancer stages but also identified the biomarker genes and gene networks implying the regulatory mechanisms in the lung cancer development. In addition, ECMarker demonstrates clinical interpretability as its prioritized biomarker genes can predict survival rates of early lung cancer patients (P-value < 0.005). Finally, we identified a number of drugs currently in clinical use for late stages or other cancers with effects on these early lung cancer biomarkers, suggesting potential novel candidates on early cancer medicine. Availabilityand implementation ECMarker is open source as a general-purpose tool at https://github.com/daifengwanglab/ECMarker. Supplementary information Supplementary data are available at Bioinformatics online.
- Published
- 2019
3. p63 is a prosurvival factor in the adult mammary gland during post-lactational involution, affecting PI-MECs and ErbB2 tumorigenesis
- Author
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Ute M. Moll, N D Marchenko, Evguenia M. Alexandrova, Alisha R. Yallowitz, S Xu, and Flaminia Talos
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STAT3 Transcription Factor ,Heterozygote ,medicine.medical_specialty ,Receptor, ErbB-2 ,Mammary gland ,Breast Neoplasms ,Mice, Transgenic ,Biology ,medicine.disease_cause ,Disease-Free Survival ,Mice ,Mammary Glands, Animal ,Pregnancy ,Internal medicine ,medicine ,Animals ,Humans ,Involution (medicine) ,Progenitor cell ,Molecular Biology ,Original Paper ,integumentary system ,Myoepithelial cell ,Epithelial Cells ,Cell Biology ,Phosphoproteins ,Epithelium ,Cell biology ,Mice, Inbred C57BL ,Disease Models, Animal ,stomatognathic diseases ,medicine.anatomical_structure ,Endocrinology ,Mammary Epithelium ,Trans-Activators ,Female ,sense organs ,Stem cell ,Carcinogenesis ,Signal Transduction - Abstract
In embryogenesis, p63 is essential to develop mammary glands. In the adult mammary gland, p63 is highly expressed in the basal cell layer that comprises myoepithelial and interspersed stem/progenitor cells, and has limited expression in luminal epithelial cells. In adult skin, p63 has a crucial role in the maintenance of epithelial stem cells. However, it is unclear whether p63 also has an equivalent role as a stem/progenitor cell factor in adult mammary epithelium. We show that p63 is essential in vivo for the survival and maintenance of parity-identified mammary epithelial cells (PI-MECs), a pregnancy-induced heterogeneous population that survives post-lactational involution and contain multipotent progenitors that give rise to alveoli and ducts in subsequent pregnancies. p63+/- glands are normal in virgin, pregnant and lactating states. Importantly, however, during the apoptotic phase of post-lactational involution p63+/- glands show a threefold increase in epithelial cell death, concomitant with increased activation of the oncostatin M/Stat3 and p53 pro-apoptotic pathways, which are responsible for this phase. Thus, p63 is a physiologic antagonist of these pathways specifically in this regressive stage. After the restructuring phase when involution is complete, mammary glands of p63+/- mice again exhibit normal epithelial architecture by conventional histology. However, using Rosa(LSL-LacZ);WAP-Cre transgenics (LSL-LacZ, lox-stop-lox β-galactosidase), a genetic in vivo labeling system for PI-MECs, we find that p63+/- glands have a 30% reduction in the number of PI-MEC progenitors and their derivatives. Importantly, PI-MECs are also cellular targets of pregnancy-promoted ErbB2 tumorigenesis. Consistent with their PI-MEC pool reduction, one-time pregnant p63+/- ErbB2 mice are partially protected from breast tumorigenesis, exhibiting extended tumor-free and overall survival, and reduced tumor multiplicity compared with their p63+/+ ErbB2 littermates. Conversely, in virgin ErbB2 mice p63 heterozygosity provides no survival advantage. In sum, our data establish that p63 is an important survival factor for pregnancy-identified PI-MEC progenitors in breast tissue in vivo.
- Published
- 2014
4. Functional Inactivation of Endogenous MDM2 and CHIP by HSP90 Causes Aberrant Stabilization of Mutant p53 in Human Cancer Cells
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Ramona Schulz, Ute M. Moll, Dun Li, Victoria Fischer, Flaminia Talos, Talia Velasco-Hernandez, and Natalia D. Marchenko
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Cancer Research ,Lactams, Macrocyclic ,Ubiquitin-Protein Ligases ,Mutant ,Article ,Mice ,RNA interference ,Cell Line, Tumor ,Neoplasms ,Benzoquinones ,Animals ,Humans ,HSP90 Heat-Shock Proteins ,HSF1 ,Molecular Biology ,Mice, Knockout ,Gene knockdown ,biology ,Ubiquitination ,Acetylation ,Proto-Oncogene Proteins c-mdm2 ,Molecular biology ,Ubiquitin ligase ,Oncology ,Cell culture ,Cancer cell ,biology.protein ,Cancer research ,Mdm2 ,Mutant Proteins ,Tumor Suppressor Protein p53 ,Molecular Chaperones - Abstract
The tight control of wild-type p53 by mainly MDM2 in normal cells is permanently lost in tumors harboring mutant p53, which exhibit dramatic constitutive p53 hyperstabilization that far exceeds that of wild-type p53 tumors. Importantly, mutant p53 hyperstabilization is critical for oncogenic gain of function of mutant p53 in vivo. Current insight into the mechanism of this dysregulation is fragmentary and largely derived from ectopically constructed cell systems. Importantly, mutant p53 knock-in mice established that normal mutant p53 tissues have sufficient enzymatic reserves in MDM2 and other E3 ligases to maintain full control of mutant p53. We find that in human cancer cells, endogenous mutant p53, despite its ability to interact with MDM2, suffers from a profound lack of ubiquitination as the root of its degradation defect. In contrast to wild-type p53, the many mutant p53 proteins which are conformationally aberrant are engaged in complexes with the HSP90 chaperone machinery to prevent its aggregation. In contrast to wild-type p53 cancer cells, we show that in mutant p53 cancer cells, this HSP90 interaction blocks the endogenous MDM2 and CHIP (carboxy-terminus of Hsp70-interacting protein) E3 ligase activity. Interference with HSP90 either by RNA interference against HSF1, the transcriptional regulator of the HSP90 pathway, or by direct knockdown of Hsp90 protein or by pharmacologic inhibition of Hsp90 activity with 17AAG (17-allylamino-17-demethoxygeldanamycin) destroys the complex, liberates mutant p53, and reactivates endogenous MDM2 and CHIP to degrade mutant p53. Of note, 17AAG induces a stronger viability loss in mutant p53 than in wild-type p53 cancer cells. Our data support the rationale that suppression of mutant p53 levels in vivo in established cancers might achieve clinically significant effects. Mol Cancer Res; 9(5); 577–88. ©2011 AACR.
- Published
- 2011
5. p73 is an essential regulator of neural stem cell maintenance in embryonal and adult CNS neurogenesis
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Ariel B. Abraham, Lena Holembowski, Ute M. Moll, Angelina V. Vaseva, Stella E. Tsirka, D Bode, W Brück, Andreas H. Scheel, Flaminia Talos, and Matthias Dobbelstein
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Central Nervous System ,Cell Survival ,Neurogenesis ,Cellular differentiation ,Mitosis ,Biology ,Hippocampus ,Article ,S Phase ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Neural Stem Cells ,Animals ,Progenitor cell ,skin and connective tissue diseases ,neoplasms ,Molecular Biology ,Cellular Senescence ,Embryonic Stem Cells ,030304 developmental biology ,Mice, Knockout ,Neurons ,0303 health sciences ,Receptors, Notch ,SOXB1 Transcription Factors ,Tumor Suppressor Proteins ,Nuclear Proteins ,Cell Differentiation ,Tumor Protein p73 ,Cell Biology ,Embryonic stem cell ,Neural stem cell ,DNA-Binding Proteins ,Neuroepithelial cell ,Adult Stem Cells ,Immunology ,Stem cell ,Neuroscience ,030217 neurology & neurosurgery ,Hydrocephalus ,Signal Transduction ,Adult stem cell - Abstract
The p53 family member p73 is essential for brain development, but its precise role and scope remain unclear. Global p73 deficiency determines an overt and highly penetrant brain phenotype marked by cortical hypoplasia with ensuing hydrocephalus and hippocampal dysgenesis. The ΔNp73 isoform is known to function as a prosurvival factor of mature postmitotic neurons. In this study, we define a novel essential role of p73 in the regulation of the neural stem cell compartment. In both embryonic and adult neurogenesis, p73 has a critical role in maintaining an adequate neurogenic pool by promoting self-renewal and proliferation and inhibiting premature senescence of neural stem and early progenitor cells. Thus, products of the p73 gene locus are essential maintenance factors in the central nervous system, whose broad action stretches across the entire differentiation arch from stem cells to mature postmitotic neurons.
- Published
- 2010
6. p63 and canonical Wnt signaling
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Flaminia Talos, Ramona Schulz, and Ute M. Moll
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Wnt signaling pathway ,LRP6 ,LRP5 ,Cell Biology ,Biology ,Molecular Biology ,Developmental Biology ,Cell biology - Published
- 2010
7. The alpha/beta carboxyterminal domains of p63 are required for skin and limb development. New insights from the Brdm2 mouse which is not a complete p63 knockout but expresses p63 gamma-like proteins
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Ute M. Moll, Flaminia Talos, Sonja Wolff, Ulrike Beyer, Gustavo Palacios, and Matthias Dobbelstein
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Gene isoform ,skin and limb development ,Biology ,Epithelium ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Forelimb ,Limb development ,Animals ,Protein Isoforms ,Molecular Biology ,Gene ,Transcription factor ,Alleles ,030304 developmental biology ,Skin ,Mice, Knockout ,0303 health sciences ,p63 ,Epidermis (botany) ,p63 C-terminal isoforms ,Cell Biology ,Phosphoproteins ,Phenotype ,Molecular biology ,Hindlimb ,Protein Structure, Tertiary ,chemistry ,030220 oncology & carcinogenesis ,Knockout mouse ,Trans-Activators ,DNA - Abstract
Udgivelsesdato: 2009-Aug p63, an ancestral transcription factor of the p53 family, has three C-terminal isoforms whose relative in vivo functions are elusive. The p63 gene is essential for skin and limb development, as vividly shown by two independent global knockout mouse models. Both strains, although constructed differently, have identical and severe phenotypes, characterized by absent epidermis and hindlimbs and only rudimentary forelimbs at birth. Here we show that mice from one model, Brdm2, express normal levels of truncated p63 proteins that contain the DNA binding and oligomerization domain but lack the long carboxy-terminal SAM (sterile alpha-motif) and post-SAM domains that are specific for the alpha and beta isoforms. As such, transcriptionally active p63 proteins from Brdm2 mice resemble the naturally occurring p63gamma isoforms, which of all the p63 isoforms most closely resemble p53. Thus, Brdm2 mice are p63alpha/beta isoform-specific knockout mice, gaining unexpected new importance. Our studies identify that p63alpha/beta but not p63gamma are absolutely required for proper skin and limb development.
- Published
- 2009
8. MIF loss impairs Myc-induced lymphomagenesis
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Ute M. Moll, Flaminia Talos, Gunter Fingerle-Rowson, Patricio Mena, and Oleksi Petrenko
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Male ,Lymphoma, B-Cell ,animal diseases ,Genes, myc ,Gene Expression ,Apoptosis ,Cell Cycle Proteins ,Mice, Transgenic ,chemical and pharmacologic phenomena ,Inflammation ,Biology ,medicine.disease_cause ,Proto-Oncogene Proteins c-myc ,Mice ,Tumor Suppressor Protein p14ARF ,In Situ Nick-End Labeling ,otorhinolaryngologic diseases ,medicine ,Animals ,E2F1 ,E2F ,Macrophage Migration-Inhibitory Factors ,Molecular Biology ,Mice, Knockout ,B-Lymphocytes ,Reverse Transcriptase Polymerase Chain Reaction ,Cell growth ,Cell Biology ,respiratory system ,medicine.disease ,biological factors ,E2F Transcription Factors ,Lymphoma ,DNA-Binding Proteins ,Mice, Inbred C57BL ,Cancer research ,Female ,Macrophage migration inhibitory factor ,Tumor Suppressor Protein p53 ,medicine.symptom ,Carcinogenesis ,Gene Deletion ,Transcription Factors - Abstract
Macrophage migration inhibitory factor (MIF) is a potent regulator of inflammation and cell growth. Using the Emu-Myc lymphoma mouse model, we demonstrate that loss of MIF markedly delays the onset of B-cell lymphoma development in vivo. The molecular basis for this MIF-loss-induced phenotype is the perturbed DNA-binding activity of E2F factors and the concomitantly enhanced tumor suppressor activity of the p53 pathway. Accordingly, premalignant MIF-null Emu-Myc B-cells are predisposed to delayed S-phase progression and increased apoptosis. MIF-deficient lymphomas that do arise under these conditions contain frequent ARF deletions and p53 inactivating mutations. Conversely, MIF expression is retained in tumors developed by wild-type Emu-Myc animals, and the presence of one or both MIF alleles is sufficient to accelerate the development of Myc-induced lymphomas. Collectively, these results indicate that MIF promotes Myc-mediated tumorigenesis, at least in the B-lymphoid compartment, and implicate MIF as a mediator of malignant cell growth in vivo.
- Published
- 2005
9. Epithelial cell lineage specification during prostate organogenesis and regeneration (210.4)
- Author
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Zhu Wang, Chee Wai Chua, Flaminia Talos, Michael M. Shen, Maho Shibata, Ming Lei, and Sarah K. Bergren
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medicine.anatomical_structure ,Prostate ,Regeneration (biology) ,Genetics ,medicine ,Organogenesis ,Biology ,Molecular Biology ,Biochemistry ,Lineage specification ,Epithelium ,Biotechnology ,Cell biology - Published
- 2014
10. Brdm2—an aberrant hypomorphic p63 allele
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Matthias Dobbelstein, Ute M. Moll, Sonja Wolff, Ulrike Beyer, and Flaminia Talos
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Genetics ,0303 health sciences ,03 medical and health sciences ,0302 clinical medicine ,integumentary system ,Epidermis (botany) ,030220 oncology & carcinogenesis ,Cell Biology ,Allele ,Biology ,Molecular Biology ,Article ,030304 developmental biology - Abstract
In response to our recent report on the Brdm2 mouse model for p63 function1, Mikkola et al.2 raise concerns on three of our statements: 1) They maintain their initial claim that no functional p63 protein of any kind is synthesized in mice homozygous for the Brdm2 allele; 2) they report the occurrence of spontaneous wild-type allelic reversions in these mice, leading to patches of completely normal epidermis, and propose that these normal reverted skin patches are in fact the multilayered epithelia we described; 3) they insist that the Brdm2 allele is phenotypically indistinguishable from a global p63 knockout.
- Published
- 2009
11. p73 is dispensable for commitment to neural stem cell fate, but is essential for neural stem cell maintenance and for blocking premature differentiation
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Evguenia M. Alexandrova, Ute M. Moll, and Flaminia Talos
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Cellular differentiation ,Induced Pluripotent Stem Cells ,Apoptosis ,Nerve Tissue Proteins ,Biology ,Nestin ,Tumor suppressor proteins ,Mice ,Intermediate Filament Proteins ,Neural Stem Cells ,Correspondence ,Animals ,Nuclear protein ,skin and connective tissue diseases ,Induced pluripotent stem cell ,neoplasms ,Molecular Biology ,Cells, Cultured ,Blocking (radio) ,Tumor Suppressor Proteins ,Nuclear Proteins ,Cell Differentiation ,Tumor Protein p73 ,Cell Biology ,Neural stem cell ,Cell biology ,DNA-Binding Proteins ,Immunology - Abstract
p73 is dispensable for commitment to neural stem cell fate, but is essential for neural stem cell maintenance and for blocking premature differentiation
- Published
- 2012
12. While p73 is essential, p63 is completely dispensable for the development of the central nervous system
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Lena Holembowski, Ute M. Moll, Flaminia Talos, Ramona Schulz, Matthias Dobbelstein, Andreas H. Scheel, and Sonja Wolff
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Programmed cell death ,Cell Survival ,Neurogenesis ,Organogenesis ,Central nervous system ,Apoptosis ,Mice, Transgenic ,Biology ,Polymerase Chain Reaction ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Neural Stem Cells ,medicine ,Animals ,Humans ,RNA, Small Interfering ,Molecular Biology ,030304 developmental biology ,0303 health sciences ,Gene knockdown ,Cell Death ,Tumor Suppressor Proteins ,Brain ,Nuclear Proteins ,Cell Differentiation ,Tumor Protein p73 ,Cell Biology ,Spinal cord ,Embryonic stem cell ,Molecular biology ,Neural stem cell ,Cell biology ,DNA-Binding Proteins ,medicine.anatomical_structure ,Spinal Cord ,Gene Knockdown Techniques ,030217 neurology & neurosurgery ,Developmental Biology ,Neuroanatomy ,Transcription Factors - Abstract
The ancient p53 paralogs p63 and p73 regulate specific tissue formation, cell survival and cell death via their TA and ΔN isoforms. Targeted disruption of the p73 locus leads to severe defects in the development of the central nervous system (CNS), and p73 has recently been shown to be an essential regulator of neural stem cell maintenance and differentiation in both embryonal and adult neurogenesis. In contrast, global p63-/- mice lack skin and limbs. Moreover, p63 is detectable in embryonic cortex. It has previously been proposed to also play critical pro-death and pro-survival roles in neural precursors of the developing sympathetic and central nervous system, respectively, based on experimental overexpression and siRNA-mediated knockdown of p63. Here we perform an extensive analysis of the developing central nervous system in global p63-/- mice and their wildtype littermates. Brain and spinal cord of embryos and newborn mice were assessed in vivo for neuroanatomy, histology, apoptosis, proliferation, stemness and differentiation, and in vitro for self-renewal and maturation in neurosphere assays. None of these analyses revealed a detectable phenotype in p63-/- mice. Hence, despite the profound impact of p63 on the development of stratified epithelia and limbs, p63 is completely dispensable for proper development of the central nervous system. Thus, despite their strong homology, the non-overlapping tissue specificity of p63 and p73 functions appears more pronounced than previously anticipated.
- Published
- 2011
13. E2F1 plays a direct role in Rb stabilization and p53-independent tumor suppression
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Ute M. Moll, Oleksi Petrenko, Flaminia Talos, Gustavo Palacios, and Alice Nemajerova
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Genome instability ,endocrine system ,DNA damage ,medicine.disease_cause ,Retinoblastoma Protein ,Article ,Mice ,medicine ,E2F1 ,Animals ,Molecular Biology ,Cells, Cultured ,Mice, Knockout ,biology ,Tumor Suppressor Proteins ,Retinoblastoma protein ,DNA replication ,E2F1 Transcription Factor ,Cell Biology ,Neoplasms, Experimental ,Phenotype ,biology.protein ,Cancer research ,biological phenomena, cell phenomena, and immunity ,Tumor Suppressor Protein p53 ,Carcinogenesis ,Developmental Biology ,DNA Damage - Abstract
To better understand the role of E2F1 in tumor formation, we analyzed spontaneous tumorigenesis in p53(-/-)E2F1(+/+) and p53(-/-)E2F1(-/-) mice. We show that the combined loss of p53 and E2F1 leads to an increased incidence of sarcomas and carcinomas compared to the loss of p53 alone. E2F1-deficient tumors show wide chromosomal variation, indicative of genomic instability. Consistent with this, p53(-/-)E2F1(-/-) primary fibroblasts have a reduced capacity to maintain genomic stability when exposed to S-phase inhibitors or genotoxic drugs. A major mechanism of E2F1's contribution to genomic integrity lies in mediating stabilization and engagement of the Rb protein.
- Published
- 2008
14. p73 suppresses polyploidy and aneuploidy in the absence of functional p53
- Author
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Ute M. Moll, Elsa R. Flores, Flaminia Talos, Oleksi Petrenko, and Alice Nemajerova
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Genome instability ,G2 Phase ,Aneuploidy ,Mitosis ,Biology ,Genomic Instability ,Genomic Stability ,Polyploidy ,03 medical and health sciences ,Mice ,0302 clinical medicine ,CDC2 Protein Kinase ,medicine ,Animals ,skin and connective tissue diseases ,neoplasms ,Molecular Biology ,Cellular Senescence ,030304 developmental biology ,0303 health sciences ,Tumor Suppressor Proteins ,Cyclin-Dependent Kinase 2 ,Nuclear Proteins ,Tumor Protein p73 ,Cell Biology ,Cell cycle ,Premature senescence ,G2-M DNA damage checkpoint ,medicine.disease ,DNA-Binding Proteins ,Cell Transformation, Neoplastic ,030220 oncology & carcinogenesis ,Cancer research ,Ploidy ,Tumor Suppressor Protein p53 ,DNA Damage - Abstract
Previous studies showed that p53 plays a central role in G1 and DNA damage checkpoints, thus contributing to genomic stability. We show here that p73 also plays a role in genomic integrity but this mechanism is manifest only when p53 is lost. Isolated p73 loss in primary cells does not induce genomic instability. Instead, it results in impaired proliferation and premature senescence due to compensatory activation of p53. Combined loss of p73 and p53 rescues these defects, but at the expense of exacerbated genomic instability. This leads to rapid increase in polyploidy and aneuploidy, markedly exceeding that of p53 loss alone. Constitutive deregulation of cyclin-Cdk activities and excess failure of the G2/M DNA damage checkpoint appear to fuel increased ploidy abnormalities upon p53/p73 loss, while primary mitotic defects do not play a causal role. These data indicate that p73 is essential for suppressing polyploidy and aneuploidy when p53 is inactivated.
- Published
- 2006
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