Machine Learning Methods for Prediction of CDK-Inhibitors

Progression through the cell cycle involves the coordinated activities of a suite of cyclin/cyclin-dependent kinase (CDK) complexes. The activities of the complexes are regulated by CDK inhibitors (CDKIs). Apart from its role as cell cycle regulators, CDKIs are involved in apoptosis, transcriptional regulation, cell fate determination, cell migration and cytoskeletal dynamics. As the complexes perform crucial and diverse functions, these are important drug targets for tumour and stem cell therapeutic interventions. However, CDKIs are represented by proteins with considerable sequence heterogeneity and may fail to be identified by simple similarity search methods. In this work we have evaluated and developed machine learning methods for identification of CDKIs. We used different compositional features and evolutionary information in the form of PSSMs, from CDKIs and non-CDKIs for generating SVM and ANN classifiers. In the first stage, both the ANN and SVM models were evaluated using Leave-One-Out Cross-Validation and in the second stage these were tested on independent data sets. The PSSM-based SVM model emerged as the best classifier in both the stages and is publicly available through a user-friendly web interface at http://bioinfo.icgeb.res.in/cdkipred.

[1]  James L. McClelland,et al.  Parallel distributed processing: explorations in the microstructure of cognition, vol. 1: foundations , 1986 .

[2]  P. S. Larson,et al.  CDKN1C/p57kip2 is a candidate tumor suppressor gene in human breast cancer , 2008, BMC Cancer.

[3]  D. Geerts,et al.  Inactivation of CDK2 is synthetically lethal to MYCN over-expressing cancer cells , 2009, Proceedings of the National Academy of Sciences.

[4]  Philipp Slusallek,et al.  Introduction to real-time ray tracing , 2005, SIGGRAPH Courses.

[5]  Mariela C. Marazita,et al.  INK4 proteins, a family of mammalian CDK inhibitors with novel biological functions , 2007, IUBMB life.

[6]  D. Lane,et al.  Inhibitors of cyclin-dependent kinases as anti-cancer therapeutics. , 2000, Current medicinal chemistry.

[7]  S. Prigge,et al.  Targeting malaria with specific CDK inhibitors. , 2005, Biochimica et biophysica acta.

[8]  G. Hannon,et al.  KAP: a dual specificity phosphatase that interacts with cyclin-dependent kinases. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[9]  R. Palmer,et al.  Introduction to the theory of neural computation , 1994, The advanced book program.

[10]  J. Adkins,et al.  Intrinsic structural disorder and sequence features of the cell cycle inhibitor p57Kip2 , 2002, Proteins.

[11]  T. Cheng,et al.  The CDK inhibitors: potential targets for therapeutic stem cell manipulations? , 2008, Gene Therapy.

[12]  James M. Roberts,et al.  CDK Inhibitors : Cell Cycle Regulators and Beyond , 2008 .

[13]  C. Bergounioux,et al.  The plant CDK inhibitor NtKIS1a interferes with dedifferentiation, is specifically down regulated during development and interacts with a JAB1 homolog , 2008 .

[14]  L. Meijer,et al.  Inhibitors of Leishmania mexicana CRK3 Cyclin-Dependent Kinase: Chemical Library Screen and Antileishmanial Activity , 2004, Antimicrobial Agents and Chemotherapy.

[15]  Thorsten Joachims,et al.  Making large scale SVM learning practical , 1998 .

[16]  K. Kehn-Hall,et al.  Inhibition of human immunodeficiency virus type-1 by cdk inhibitors , 2010, AIDS research and therapy.

[17]  Campbell McInnes,et al.  Progress in the evaluation of CDK inhibitors as anti-tumor agents. , 2008, Drug discovery today.

[18]  R. Matusik,et al.  Down-regulation of p57Kip2 induces prostate cancer in the mouse. , 2008, Cancer research.

[19]  Roger Brent,et al.  C dil, a Human Gl and S Phase Protein Phosphatase That Associates with Cdk2 , 2003 .

[20]  Dinesh Gupta,et al.  LipocalinPred: a SVM-based method for prediction of lipocalins , 2009, BMC Bioinformatics.

[21]  Dinesh Gupta,et al.  CyclinPred: A SVM-Based Method for Predicting Cyclin Protein Sequences , 2008, PloS one.

[22]  Gajendra P.S. Raghava,et al.  Prediction of RNA binding sites in a protein using SVM and PSSM profile , 2008, Proteins.

[23]  Hiroyuki Tanaka,et al.  Overexpression of cdk Inhibitor p16INK4aby Adenovirus Vector Inhibits Cardiac Hypertrophy in vitro and in vivo: a Novel Strategy for the Gene Therapy of Cardiac Hypertrophy , 2001 .

[24]  Tom Fawcett,et al.  An introduction to ROC analysis , 2006, Pattern Recognit. Lett..

[25]  Shunichi Takeda,et al.  Cyclin-dependent kinases and cell-cycle transitions: does one fit all? , 2008, Nature Reviews Molecular Cell Biology.

[26]  Robert Wysocki,et al.  CDK Pho85 targets CDK inhibitor Sic1 to relieve yeast G1 checkpoint arrest after DNA damage , 2006, Nature Structural &Molecular Biology.

[27]  Vladimir Vapnik,et al.  Statistical learning theory , 1998 .

[28]  Maurizio Recanatini,et al.  Role of phosphorylated Thr160 for the activation of the CDK2/Cyclin A complex , 2005, Proteins.

[29]  A. Tyner,et al.  Tumor suppressor functions for the Cdk inhibitor p21 in the mouse colon , 2004, Oncogene.

[30]  P. Fischer,et al.  CDK inhibitors in clinical development for the treatment of cancer , 2003, Expert opinion on investigational drugs.

[31]  J A Swets,et al.  Measuring the accuracy of diagnostic systems. , 1988, Science.

[32]  D. Inzé,et al.  SIAMESE, a Plant-Specific Cell Cycle Regulator, Controls Endoreplication Onset in Arabidopsis thaliana[W] , 2006, The Plant Cell Online.

[33]  Adam Godzik,et al.  Cd-hit: a fast program for clustering and comparing large sets of protein or nucleotide sequences , 2006, Bioinform..

[34]  S. Marx,et al.  Rare germline mutations in cyclin-dependent kinase inhibitor genes in multiple endocrine neoplasia type 1 and related states. , 2009, The Journal of clinical endocrinology and metabolism.

[35]  S. Elledge,et al.  p57KIP2, a structurally distinct member of the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor gene. , 1995, Genes & development.

[36]  B. Schölkopf,et al.  Advances in kernel methods: support vector learning , 1999 .

[37]  Terry Gaasterland,et al.  Prediction of Cyclin-Dependent Kinase Phosphorylation Substrates , 2007, PloS one.

[38]  L. Holm,et al.  The Pfam protein families database , 2005, Nucleic Acids Res..

[39]  C. Naula,et al.  Protein kinases as drug targets in trypanosomes and Leishmania. , 2005, Biochimica et biophysica acta.

[40]  T. Hunter,et al.  Dephosphorylation of Cdk2 Thr160 by the Cyclin-Dependent Kinase-Interacting Phosphatase KAP in the Absence of Cyclin , 1995, Science.

[41]  K. Nakayama,et al.  Cip/Kip cyclin‐dependent kinase inhibitors: brakes of the cell cycle engine during development , 1998, BioEssays : news and reviews in molecular, cellular and developmental biology.