title: The cyclin D1-CDK4 oncogenic interactome enables identification of potential novel oncogenes and clinical prognosis.
abstract: Overexpression of cyclin D1 and its catalytic partner, CDK4, is frequently seen in human cancers. We constructed cyclin D1 and CDK4 protein interaction network in a human breast cancer cell line MCF7, and identified novel CDK4 protein partners. Among CDK4 interactors we observed several proteins functioning in protein folding and in complex assembly. One of the novel partners of CDK4 is FKBP5, which we found to be required to maintain CDK4 levels in cancer cells. An integrative analysis of the extended cyclin D1 cancer interactome and somatic copy number alterations in human cancers identified BAIAPL21 as a potential novel human oncogene. We observed that in several human tumor types BAIAPL21 is expressed at higher levels as compared to normal tissue. Forced overexpression of BAIAPL21 augmented anchorage independent growth, increased colony formation by cancer cells and strongly enhanced the ability of cells to form tumors in vivo. Lastly, we derived an Aggregate Expression Score (AES), which quantifies the expression of all cyclin D1 interactors in a given tumor. We observed that AES has a prognostic value among patients with ER-positive breast cancers. These studies illustrate the utility of analyzing the interactomes of proteins involved in cancer to uncover potential oncogenes, or to allow better cancer prognosis.
authors.affiliation: a Department of Pharmacology; Faculty of Medicine Siriraj Hospital ; Mahidol University ; Bangkok , Thailand.
authors.forename: Siwanon
authors.initials: S
authors.lastname: Jirawatnotai
authors.forename: Samanta
authors.initials: S
authors.lastname: Sharma
authors.forename: Wojciech
authors.initials: W
authors.lastname: Michowski
authors.forename: Bhoom
authors.initials: B
authors.lastname: Suktitipat
authors.forename: Yan
authors.initials: Y
authors.lastname: Geng
authors.forename: John
authors.initials: J
authors.lastname: Quackenbush
authors.forename: Joshua E
authors.initials: JE
authors.lastname: Elias
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.forename: Yaoyu E
authors.initials: YE
authors.lastname: Wang
authors.forename: Piotr
authors.initials: P
authors.lastname: Sicinski
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism*; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism*; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008819:Mice, Nude; D008840:Microfilament Proteins / Q000378:metabolism; D009857:Oncogenes; D011379:Prognosis; D011485:Protein Binding; D060066:Protein Interaction Maps; D011960:Receptors, Estrogen / Q000378:metabolism; D016019:Survival Analysis; D022021:Tacrolimus Binding Proteins / Q000378:metabolism; D000099159:Tacrolimus Binding Protein 5
chemical_list: D019938:Cyclin D1; D051358:Cyclin-Dependent Kinase 4; D008840:Microfilament Proteins; D011960:Receptors, Estrogen; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5; C523100:BAIAP2L1 protein, human; C495900:CDK4 protein, human
keywords: ACN, acetonitrile; AES, aggregate expression score; ATCC, American type culture collection; CDK4; DMEM, Dulbecco's Modified Eagle's medium; FBS, fetal bovine serum; LC-MS/MS, liquid chromatography-tandem mass spectrometry; PPI, protein-protein interaction; RPMI, Roswell Park Memorial Institute medium; SCNA, somatic copy-number variation; TCGA, the cancer genome atlas; WB, immunoblotting; breast cancer; cyclin D1; interactome; oncogenes; oncogenic signature; siFKBP4, FKBP4-specific small interfering RNA; siFKBP5, FKBP5-specific small interfering RNA; siRNA, small interfering RNA; sicont, control small interfering RNA; sicyclin D1, cyclin D1-specific small interfering RNA