The Open Cell Signaling Journal

2010, 2 : 1-12
Published online 2010 April 2. DOI: 10.2174/1876390101002010001
Publisher ID: TOCELLSJ-2-1

RESEARCH ARTICLE
 Importance of CDK7 for G1 Re-Entry into the Mammalian Cell Cycle and Identification of New Downstream Networks Using a Computational Method

Hideko Sone, *,1,2 , Tomokazu Fukuda3 , Hiroyoshi Toyoshiba11 , Takeharu Yamanaka1 , Fred Parham1 and Christopher J Portier1
1 Laboratory of Computational Biology and Risk Analysis, National Institute of Environmental Health Sciences, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709, USA
2 Health Effects Team, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba 305-8506, Japan
3 Laboratory of Animal breeding and Genetics, Graduate school of Agricultural Science, Tohoku University, Tsutsumidori-amamiyamachi 1-1 Aoba-ku, Sendai 981-8555, Japan

* Address correspondence to this author at the Research Center for Environmental Risk, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba 305-8506, Japan; Tel: +81.298.50.2464; Fax: +81.298.50.2546; E-mail: hsone@nies.go.jp

ABSTRACT

Many of the key molecules in cell cycle progression (e.g. pRB, cyclin complexes) and their basic interactions are oncogene or tumor suppressor genes, which are well characterized in the clinical and experimental analysis. However, there are still unknown mechanisms for the cell cycle regulation, which is critical step for the progression of the cancer development. Especially it is not fully understood how the cells move to G1 phase from quiescent G0 phase in the mammalian cells. To find out the new gene networks associated with the two transition of the mammalian cell cycle (G0 to G1 and G1 to S phase), we analyzed the linkages between 39 representative oncogene or tumor suppressor genes, which related to the cell cycle regulation, with gene expression sets obtained from the publicly opened microarray data for mouse embryonic fibroblasts that synchronized by the serum starvation or hydroxyurea treatment. Analyses with a qualitative algorithm based on Bayesian networks that assume a log-linear relationship between genes have applied, and newly found networks were validated. Results highlighted the importance of two master genes, Cdk7 and Cdkna2 for the re-entry to G1 from G0, and suggested a new network connection from Cdk7 to downstream molecules, including the EGF receptor and N-myc. Introduction of a recombinant Cdk7 with retrovirus decreased endogenous EGFR and N-myc protein levels. The results supported the computational prediction of the Cdk7 network. Taken together, these result showed the existence of new regulating pathway from Cdk7 to Egfr and N-myc, suggesting this analytical approach provides an assessment of regulatory networks in complex mammalian cells, and the process of the carcinogenesis.

Keywords:

Gene network, cell cycle, Cdk7, mammalian, Bayesian theory.