Cell cycle gene expression networks discovered using systems biology: Significance in carcinogenesis

Abstract

The early stages of carcinogenesis are linked to defects in the cell cycle. A series of cell cycle checkpoints are involved in this process. The G1/S checkpoint that serves to integrate the control of cell proliferation and differentiation is linked to carcinogenesis and the mitotic spindle checkpoint is associated with the development of chromosomal instability. This paper presents the outcome of systems biology studies designed to evaluate if networks of covariate cell cycle gene transcripts exist in proliferative mammalian tissues including mice, rats, and humans. The GeneNetwork website that contains numerous gene expression datasets from different species, sexes, and tissues represents the foundational resource for these studies (www.genenetwork.org). In addition, WebGestalt, a gene ontology tool, facilitated the identification of expression networks of genes that co-vary with key cell cycle targets, especially Cdc20 and Plk1 (www.bioinfo.vanderbilt.edu/webgestalt). Cell cycle expression networks of such covariate mRNAs exist in multiple proliferative tissues including liver, lung, pituitary, adipose, and lymphoid tissues among others but not in brain or retina that have low proliferative potential. Sixty-three covariate cell cycle gene transcripts (mRNAs) compose the average cell cycle network with P = e(-13) to e(-36) . Cell cycle expression networks show species, sex and tissue variability, and they are enriched in mRNA transcripts associated with mitosis, many of which are associated with chromosomal instability.

Figure 1. BXD female mouse liver

Cell cycle expression network for Cdc20 covariates with correlation coefficients >0.50. The 75 cell cycle mRNAs that comprise this network are: Cdc20, Lig1, Ube2c, Mapre3, Cdca8, Casc5, 9930021A08Rik (Ubr2), Fancm, Sgol2, Jtb, Ptp4a1, 2410004L17Rik (Esco2), Pkmyt1, Sgol1, Mcm5, Cryaa, Psrc1, Ccng2, Chtf18, 5830426I05Rik (Ncapg2), Ska3, 1500003O22Rik (Rrp8), Melk, Plk1, Mastl, Birc5, Cdca5, Nek2, Rec8, Sept9, 4930563F16Rik (Dixdc1), Ncapg, Trip13, Aurkb, Ncapd2, Cenpe, Mcm2, Sept5, Kif20b, Npm1, BC027246 (Rfwd3), 1700022L09Rik (Dsn1), Cit, Ccnb2, Incenp, Spag5, Cdc25c, Cdkn1c, BC025462 (Fanci), Zwilch, Ccna2, Mcm7, Mki67, Stmn1, Nuf2, Ect2, Cdk1, Anapc2, Uhrf1, Ckap2, Aurka, Cenpf, Nusap1, Zfp318, Prc1, Plk4, Cenph, Ccnb1, Tpx2, Cdca2, Fignl1, Racgap1, Ptpn6, Pml, and 7330406P05Rik (Appl1). In the following network graph and in subsequent graphs, the various mRNA transcripts of the network can show an either positive (red and orange) or negative (blue and green) covariance. Correlation coefficients for these cell cycle gene transcript interactions are: red + >0.7, orange + >0.5 and blue - >0.7, green - >0.5.

Figure 2. BXD male mouse liver

Cell cycle expression network for Cdc20 covariates with correlation coefficients >0.50. The 44 cell cycle mRNAs that comprise this network are: Cdc20, Ube2c, Ccnb2, Spag5, 120008O12Rik (Cep55), Cdca8, Cdc25c, D1Ertd8e (Sgol2), Ccna2, Cul4a, Mki67, Stmn1, Nuf2, Sgol1, Mcm5, Ect2, Cdc2a (Cdk1), Psrc1, Uhrf1, Asz1, Aurka, Cenpf, Nusap1, Plk1, Prc1, Rbl1, Dscc1, Plk4, Birc5, Cdca5, Nek2, Tpx2, Cenph, Ncapg, Fignl1, Aurkb, Mcm4, Cenpe, Racgap1, Mcm2, Fem1b, Kif20b (Mphosh1), Cyp26b1, and Sept11.

Figure 3. BHHBF2 male mouse liver

Cell cycle expression network for Cdc20 covariates with correlation coefficients >0.50. The 70 cell cycle mRNAs that comprise this network are: Cdc20, Lig1, Exo1, Cep192, Ube2c, Cdca8, Casc5, Sgol2, Pkmyt1, Sgol1, Psrc1, Mcm6, Chtf18, Tacc3, Kntc2 (Ndc80), Melk, Plk1, Anin, Rad51, Aspm, Kif2c, Cdca5, Birc5, Nek2, Ncapg, Trip13, Ncapd2, 2810433K01Rik (Ska1), Cenpe, Mcm2, Mphosph1 (Kif20b), Cdcc99, 3000004O01Rik (Kif18b), 1700022L09Rik (Dsn1), Clspn, E2f1, Ccnb2, Kif11, BC025462 (Fanci), Ccna2, Zwilch, Mki67, Stmn1, Nuf2, Ect2, Cdc2a (Cdk1), 2310007D09Rik (Fam83d), Uhrf1, Ckap2, Aurka, Prkce, D3Ertd750e, 2610040C18Rik (Apitd1), Erc6l, Nusap1, Cdc7, Mad2l1, Bccip, UNg2 (Ccno), Mx1, Cdca3, Ccnb1, Fignl1, Racgap1, Anapc5, Cenpa, 1700007E06Rik (Syce3), Dbf4, Espl1, and Fgf10.

Figure 4. Mouse Diversity Panel Liver

Cell cycle expression network for Plk1 covariates with correlation coefficients >0.50. The 29 cell cycle mRNAs that comprise this network are: Plk1, Lig1, Pard6g, Nusap1, Cenpf, Exo1, Cdc20, 2600017H08Rik (Spc25), Prc1, Ube2c, Spag5, Kif2c, Cdca8, Cdc25c, Cdca5, Birc5, Tgfa, Ccna2, Tpx2, Mki67, Gpsm2, 241994I17Rik (Esco2), Nuf2, Sgol1, Aurkb, Cenpe, Cdk1, Hmg20b, and Mcm6.

Figure 5. Rat HXBBXH Liver

Cell cycle expression network for Cdc20 covariates with correlation coefficients >0.50. The 93 cell cycle mRNAs that comprise this network are: Cdc20, Apbb2, Aspm, Cdkn2c, Cdkn3, Cdt1, Cenpk, Cenpm, Aurka, Aurkb, BG377427 (Cenpf), Pim3, Plk1, Plk3, Bric5, Brca2, Bub1, Ccdc5, Ccdc99, Ccnb2, Mcm7, Mdc1, Melk, Mki67, Ccnd1, Cdc16, Cdc2, Ckap2, Cks2, Clk4, Dact1, Digap5, Dscc1, Rrm2, Smc2, Sox4, Spag5, Dynlt1, E2f1, Ect2, Espl1, Ezh2, Fancd2, Foxm1, Lig1, Mad2l1, Map4, Mcm2, Gadd45g, Gmnn, Hmgb2, Itgb3bp, Kif11, Kif20b, Kif23, Kif2c, Kifc1, LOC689399 (Cenpw), Mcm4, Mcm5, Mcm6, Mphosph10, Myc, Ncaph, Cdc45l, Cdca2, Nuf2, Nusap1, Prc1, Pttg1, Racgap1, Rad51, Ddx11, Dgkz, Rassf4, Rbl1, Spc25, Tacc3, Taf1, Top2a, Ccna2, Ccnb1, Traf4af1, Trip13, Tsc2, Ube2c, Ufd1l, Cdc37, Cdca3, Cdca7, Usp2, Znf655, and Zwilch.

Figure 6. BXD lung

Cell cycle expression network for Cdc20 covariates with correlation coefficients >0.50. The 102 cell cycle mRNAs that comprise this network are: Cdc20, C12orf32 (Rhno1), Cdk2, Kif23, Spc25, Ube2c, Cdca8, Cep55, C79407 (Mis18bp1), Sgol2, Gpsm2, Esco2, Sgol1, Mcm5, Chek1, 5830416I05Rik (Ncapg2), Klhl13, Tacc3, Ndc80 (Kntc2), Melk, Slbp, Casp3, E2f7, Plk1, Anin, Mastl, 8430435B07Rik (Gas213), Rad51, Aspm, Kif2c, Gsg2, Birc5, Cdca5, D030034H08 (Iqgap3), Cdc45, Mapre2, 5730507H05Rik (Ncapg), Trip13, Aurkb, 2810433K01Rik (Ska1), Cenpe, Kif20b, Cpeb1, Cdkn3 2600001J17Rik (Ccdc99), 2810047L02Rik (Dtl), Usp2, 3000004C01Rik (Kif18b), Rfwd3, Adam17, Clspn, Ncaph (Brrn1) Ccnb2, Incenp, Spag5, Fbxo5, Cks1b, Kif11, Ccna2, Mki67, Mcm7, Stmn1, Abl1, Cdca1 (Nuf2), Sox4, Ect2, Cdc2a (Cdk1), Smc2, Uhrf1, Rb1cc1, Marveld1, Ckap2, Aurka, D2Ertd750e, Brca1, 4432406C08Rik (E2f8), Ezh2, BC004701 (Ercc61), Mad2l1, Nusap1, Cenpf, Prc1, 2610036L11Rik (Cenpw), Plk4, Wee1, 2410030K01Rik (Spc24), Cdca3, Ccnb1, Tpx2, E2f3, H2afx, Pole, Cdca2, Fignl1, Racgap1, Bub1, Ccnf, Cenpa, Hells, Espl1, Mapk12, and Foxm1.

Figure 7. BXD pituitary

Cell cycle expression network for Cdc20 covariates with correlation coefficients >0.50. The 32 cell cycle mRNAs that comprise this network are: Cdc20, Kif18b, Kif23, Spc25, Ube2c, Ncaph (Brnn1), Ube2s, Cep55, C79407 (Mis18bp1), Sgol2, Mki67, Kntc1, Mcm5, Ect2, Cdk1, Anapc2(Affy_10342641), Aurka, Pmf1, Plk1, Wfs1, Prc1, Katnb1, Digap5, Cdc45, Cdca3, Cenpe, Cdt1, Mcm2, Bub1, Cenpa, Ddb1, and Dtl.

Figure 8. BHHBF2 mouse adipose tissue

a. Cell cycle expression network in females for Cdc20 covariates with correlation coefficients >0.70. The 42 cell cycle mRNAs that comprise this network are: Cdc20, 300004C01Rik (Kif18b), Exo1, Clspn, Cit, Ncaph, Ccnb2, Cdca8, Casc5, Csk2, Sgol2, BC025462 (Facni), Kif11, Ccna2, Mki67, Kntc1, Cdca1 (Nuf2), Sgol1, Cdk1, Psrc1, Uhrf1, Aurka, D2Ertd750e, Tacc3, E2f8, Melk, Plk1, Rad51, Aspm, Cdca5, Birc5, Cdca3, Cenph, Trip13, Fignl1, 2810443K01Rik (Ska1), Cenpe, Racgap1, Kif20b (Mphosph1), Ccdc99, Dbf4, and Espl1. b. Cell cycle expression network in males for Cdc20 covariates with correlation coefficients >0.70. The 42 cell cycle mRNAs that comprise this network are: Cdc20, Exo1, Clspn, Cit, Ccnb2, Cdca8, Csk2, Kif11, BC025462 (Fanci), Ccna2, Sgol1, Aif1, Nuf2 (Cdca1), Mcm5, Psrc1, Cdk1, Mcm6, Uhrf1, Aurka, Tacc3, D2Ertd750e, E2f8, Melk, Plk1, Rad51, Aspm, Cdca5, Birc5, Gmnn, Cdca3, Cenph, Trip13, Fignl1, Mcm4, Cenpe, Racgap1, Mcm2, Cenpa, Ptpn6, Ccdc99, Dbf4 and Espl1.

Figure 8. BHHBF2 mouse adipose tissue

a. Cell cycle expression network in females for Cdc20 covariates with correlation coefficients >0.70. The 42 cell cycle mRNAs that comprise this network are: Cdc20, 300004C01Rik (Kif18b), Exo1, Clspn, Cit, Ncaph, Ccnb2, Cdca8, Casc5, Csk2, Sgol2, BC025462 (Facni), Kif11, Ccna2, Mki67, Kntc1, Cdca1 (Nuf2), Sgol1, Cdk1, Psrc1, Uhrf1, Aurka, D2Ertd750e, Tacc3, E2f8, Melk, Plk1, Rad51, Aspm, Cdca5, Birc5, Cdca3, Cenph, Trip13, Fignl1, 2810443K01Rik (Ska1), Cenpe, Racgap1, Kif20b (Mphosph1), Ccdc99, Dbf4, and Espl1. b. Cell cycle expression network in males for Cdc20 covariates with correlation coefficients >0.70. The 42 cell cycle mRNAs that comprise this network are: Cdc20, Exo1, Clspn, Cit, Ccnb2, Cdca8, Csk2, Kif11, BC025462 (Fanci), Ccna2, Sgol1, Aif1, Nuf2 (Cdca1), Mcm5, Psrc1, Cdk1, Mcm6, Uhrf1, Aurka, Tacc3, D2Ertd750e, E2f8, Melk, Plk1, Rad51, Aspm, Cdca5, Birc5, Gmnn, Cdca3, Cenph, Trip13, Fignl1, Mcm4, Cenpe, Racgap1, Mcm2, Cenpa, Ptpn6, Ccdc99, Dbf4 and Espl1.

Figure 9. Human lymphoblasts

Cell cycle expression network of 57 Cdc20 covariates with correlation coefficients >0.50. These mRNAs include: Cdc20, Casp3, Pdcd6ip, Hjurp, Tubb4b, Dynlt3, Cenpf, Cdca8, Tpx2, Smarca4, Kif23, Gsg2, Gpsm2, Kif2c, Spag5, Ckap5, Rcc2, Ccna2, Setd8, Prc1, Kif22, Ppm1a, Kntc1, Cdc25b, Uhrf1, Trip13, Tacc3, Hcfc1, Plk1, Cenpa, Tnfaip3, Rps27l, Kif20a, Aspm, Pbk, Miki67, Cdca2, Kif20b, Pbrm1, Aurkb, Pole, Birc5, Rbl1, Tfdp1, H2afx, Hdac1, Aurka, Cenpe, Ube2s, Nup37, Ube2c, E2f2, Ccnb2, Espl1, Ctbp1, Suv39h1, and Melk.