Cancer esearch rated Systems and Technologies blastoma-Specific Protein Interaction Network Identifies A and CSK 21 as Connecting Molecules between R l Cycle – Associated Genes

Glioblastoma (GBM; grade IV astrocytoma) is a very aggressive form of brain cancer with a poor survival and few qualified predictive markers. This study integrates experimentally validated genes that showed specific upregulation in GBM along with their protein-protein interaction information. A system level analysis was used to construct GBM-specific network. Computation of topological parameters of networks showed scale-free pattern and hierarchical organization. From the large network involving 1,447 proteins, we synthesized subnetworks and annotated them with highly enriched biological processes. A careful dissection of the functional modules, important nodes, and their connections identified two novel intermediary molecules CSK21 and protein phosphatase 1 alpha (PP1A) connecting the two subnetworks CDC2-PTEN-TOP2A-CAV1-P53 and CDC2-CAV1-RB-P53-PTEN, respectively. Real-time quantitative reverse transcription-PCR analysis revealed CSK21 to be moderately upregulated and PP1A to be overexpressed by 20-fold in GBM tumor samples. Immunohistochemical staining revealed nuclear expression of PP1A only in GBM samples. Thus, CSK21 and PP1A, whose functions are intimately associated with cell cycle regulation, might play key role in gliomagenesis.

[1]  R. Britto,et al.  Upregulation of ASCL1 and inhibition of Notch signaling pathway characterize progressive astrocytoma , 2005, Oncogene.

[2]  P. Kondaiah,et al.  PBEF1/NAmPRTase/Visfatin: A potential malignant astrocytoma/glioblastoma serum marker with prognostic value , 2008, Cancer biology & therapy.

[3]  V Martinez-Glez,et al.  Microarray gene expression profiling in meningiomas and schwannomas. , 2008, Current medicinal chemistry.

[4]  S. Gollin,et al.  Gene amplification and overexpression of protein phosphatase 1α in oral squamous cell carcinoma cell lines , 2006, Oncogene.

[5]  Yuan Qi,et al.  Integrated Genomic Analysis Identifies Clinically Relevant Subtypes of Glioblastoma Characterized by Abnormalities in PDGFRA , IDH 1 , EGFR , and NF 1 Citation Verhaak , 2010 .

[6]  B. Scheithauer,et al.  The 2007 WHO classification of tumours of the central nervous system , 2007, Acta Neuropathologica.

[7]  M. Bollen,et al.  Functional diversity of protein phosphatase-1, a cellular economizer and reset button. , 2004, Physiological reviews.

[8]  A. Nairn,et al.  PP1-mediated dephosphorylation of phosphoproteins at mitotic exit is controlled by inhibitor-1 and PP1 phosphorylation , 2009, Nature Cell Biology.

[9]  J. Leal,et al.  PPP1CA contributes to the senescence program induced by oncogenic Ras. , 2007, Carcinogenesis.

[10]  Thomas D. Wu,et al.  Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. , 2006, Cancer cell.

[11]  Steven J. M. Jones,et al.  Phosphorylated caveolin-1 regulates Rho/ROCK-dependent focal adhesion dynamics and tumor cell migration and invasion. , 2008, Cancer research.

[12]  P. Lichter,et al.  Expression analysis of imbalanced genes in prostate carcinoma using tissue microarrays , 2006, British Journal of Cancer.

[13]  Gregory W. Corder,et al.  Nonparametric Statistics for Non-Statisticians: A Step-by-Step Approach , 2009 .

[14]  A. Barabasi,et al.  Network biology: understanding the cell's functional organization , 2004, Nature Reviews Genetics.

[15]  Mark Gerstein,et al.  The Importance of Bottlenecks in Protein Networks: Correlation with Gene Essentiality and Expression Dynamics , 2007, PLoS Comput. Biol..

[16]  J. Leal,et al.  Characterization of the p53 Response to Oncogene-Induced Senescence , 2008, PloS one.

[17]  Carlos Prieto,et al.  APID2NET: unified interactome graphic analyzer , 2007, Bioinform..

[18]  D. Litchfield,et al.  Protein Kinase CK2 in Health and Disease , 2009, Cellular and Molecular Life Sciences.

[19]  T. Barrette,et al.  Mining for regulatory programs in the cancer transcriptome , 2005, Nature Genetics.

[20]  M. Teitell,et al.  Reciprocal Regulation of SOCS 1 and SOCS3 Enhances Resistance to Ionizing Radiation in Glioblastoma Multiforme , 2007, Clinical Cancer Research.

[21]  D. Nelson,et al.  Control and activity of type-1 serine/threonine protein phosphatase during the cell cycle. , 1995, Seminars in cancer biology.

[22]  A. McCluskey,et al.  Serine-threonine protein phosphatase inhibitors: development of potential therapeutic strategies. , 2002, Journal of medicinal chemistry.

[23]  Patricia T W Cohen,et al.  Protein phosphatase 1--targeted in many directions. , 2002, Journal of cell science.

[24]  W. Kruskal,et al.  Use of Ranks in One-Criterion Variance Analysis , 1952 .

[25]  James S. Duncan,et al.  Too much of a good thing: the role of protein kinase CK2 in tumorigenesis and prospects for therapeutic inhibition of CK2. , 2008, Biochimica et biophysica acta.

[26]  P. Kleihues,et al.  Primary and secondary glioblastomas: from concept to clinical diagnosis. , 1999, Neuro-oncology.

[27]  William Arbuthnot Sir Lane,et al.  Direct identification of PTEN phosphorylation sites , 2002, FEBS letters.

[28]  M. Lisanti,et al.  In vitro phosphorylation of caveolin-rich membrane domains: identification of an associated serine kinase activity as a casein kinase II-like enzyme. , 1994, Oncogene.

[29]  O. Kallioniemi,et al.  Identification of differentially expressed genes in human gliomas by DNA microarray and tissue chip techniques. , 2000, Cancer research.

[30]  H. Armah.  Worse Outcome in Primary Glioblastoma Multiforme With Concurrent Epidermal Growth Factor Receptor and p53 Alteration , 2010 .

[31]  R. Britto,et al.  Novel Glioblastoma Markers with Diagnostic and Prognostic Value Identified through Transcriptome Analysis , 2008, Clinical Cancer Research.

[32]  P. Shannon,et al.  Cytoscape: a software environment for integrated models of biomolecular interaction networks. , 2003, Genome research.

[33]  S. Gabriel,et al.  Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. , 2010, Cancer cell.

[34]  D. Dressman,et al.  Overexpression of the EGFR/FKBP12/HIF-2alpha pathway identified in childhood astrocytomas by angiogenesis gene profiling. , 2003, Cancer research.

[35]  Fidel Ramírez,et al.  Computing topological parameters of biological networks , 2008, Bioinform..

[36]  L. Chin,et al.  Marked genomic differences characterize primary and secondary glioblastoma subtypes and identify two distinct molecular and clinical secondary glioblastoma entities. , 2006, Cancer research.

[37]  K. Thennarasu,et al.  Grade-Specific Expression of Insulin-like Growth Factor–Binding Proteins-2, -3, and -5 in Astrocytomas: IGFBP-3 Emerges as a Strong Predictor of Survival in Patients with Newly Diagnosed Glioblastoma , 2010, Cancer Epidemiology, Biomarkers & Prevention.

[38]  T. Ideker,et al.  Network-based classification of breast cancer metastasis , 2007, Molecular systems biology.

[39]  Wun-Jae Kim,et al.  Molecular biomarkers in urothelial bladder cancer , 2008, Cancer science.

[40]  T. Thompson,et al.  Caveolin-1 Maintains Activated Akt in Prostate CancerCells through Scaffolding Domain Binding Site Interactions with andInhibition of Serine/Threonine Protein Phosphatases PP1 andPP2A , 2003, Molecular and Cellular Biology.

[41]  S. Horvath,et al.  Analysis of oncogenic signaling networks in glioblastoma identifies ASPM as a molecular target , 2006, Proceedings of the National Academy of Sciences.

[42]  R. Sposto,et al.  A limited screen for protein interactions reveals new roles for protein phosphatase 1 in cell cycle control and apoptosis. , 2007, Journal of proteome research.

[43]  Giovanni Scardoni,et al.  Analyzing biological network parameters with CentiScaPe , 2009, Bioinform..

[44]  Zhaolei Zhang,et al.  An atlas of chaperone–protein interactions in Saccharomyces cerevisiae: implications to protein folding pathways in the cell , 2009, Molecular systems biology.