Transcriptional regulation of AKT activation by E2F.

The pRB-E2F pathway is a downstream target of mitogenic signaling pathways. The E2F family of transcription factors has a pivotal role in regulating cell proliferation since it controls the timely expression of many genes that are required for cell cycle progression. Moreover, at least one member of this family, E2F1, can mediate apoptotic cell death. We show here that E2F also modulates the activity of a major signal transduction pathway: we demonstrate that E2F upregulates AKT activity through a transcription-dependent mechanism. We identify the adaptor protein Grb2 associated binder 2 (Gab2) as a direct E2F target gene and an essential effector of E2F-dependent AKT activation. AKT activation was shown to inhibit E2F1induced apoptosis. Therefore, our results suggest the existence of a negative feedback loop involving E2F and AKT.

[1]  B. Neel,et al.  The "Gab" in signal transduction. , 2003, Trends in cell biology.

[2]  Y. Kalma,et al.  Expression analysis using DNA microarrays demonstrates that E2F-1 up-regulates expression of DNA replication genes including replication protein A2 , 2001, Oncogene.

[3]  J. Nevins,et al.  The E2F1–3 transcription factors are essential for cellular proliferation , 2001, Nature.

[4]  D. Ginsberg,et al.  Up-regulation of Bcl-2 Homology 3 (BH3)-only Proteins by E2F1 Mediates Apoptosis* , 2004, Journal of Biological Chemistry.

[5]  J. Laine,et al.  The protooncogene TCL1 is an Akt kinase coactivator. , 2000, Molecular cell.

[6]  H. Iwasaki,et al.  Critical role for Gab2 in transformation by BCR/ABL. , 2002, Cancer cell.

[7]  T. Volkert,et al.  E2F integrates cell cycle progression with DNA repair, replication, and G(2)/M checkpoints. , 2002, Genes & development.

[8]  N. Dyson.  The regulation of E2F by pRB-family proteins. , 1998, Genes & development.

[9]  J. Nevins,et al.  Specificity in the activation and control of transcription factor E2F-dependent apoptosis , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[10]  K. Helin,et al.  Suppression of the p53- or pRB-mediated G1 checkpoint is required for E2F-induced S-phase entry , 2002, Nature Genetics.

[11]  B. Neel,et al.  New Role for Shc in Activation of the Phosphatidylinositol 3-Kinase/Akt Pathway , 2000, Molecular and Cellular Biology.

[12]  D. Livingston,et al.  Binding to DNA and the retinoblastoma gene product promoted by complex formation of different E2F family members. , 1993, Science.

[13]  Rosalie C Sears,et al.  Signaling Networks That Link Cell Proliferation and Cell Fate* , 2002, The Journal of Biological Chemistry.

[14]  Andrius Kazlauskas,et al.  PDGF induces an early and a late wave of PI 3-kinase activity, and only the late wave is required for progression through G1 , 1999, Current Biology.

[15]  Yong Liao,et al.  HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation , 2001, Nature Cell Biology.

[16]  J. C. Pratt,et al.  Essential role for Gab2 in the allergic response , 2001, Nature.

[17]  K. Helin,et al.  Apaf-1 is a transcriptional target for E2F and p53 , 2001, Nature Cell Biology.

[18]  D. Ginsberg.  E2F1 pathways to apoptosis , 2002, FEBS letters.

[19]  J. Slingerland,et al.  Multiple Roles of the PI3K/PKB (Akt) Pathway in Cell Cycle Progression , 2003, Cell cycle.

[20]  Rakesh Nagarajan,et al.  Mechanisms of transcriptional regulation by Rb-E2F segregate by biological pathway , 2003, Oncogene.

[21]  S. R. Datta,et al.  Cellular survival: a play in three Akts. , 1999, Genes & development.

[22]  B. Neel,et al.  The docking protein Gab2 is overexpressed and estrogen regulated in human breast cancer , 2002, Oncogene.

[23]  F. Christians,et al.  E2Fs regulate the expression of genes involved in differentiation, development, proliferation, and apoptosis. , 2001, Genes & development.

[24]  Ramana V. Davuluri,et al.  Direct coupling of the cell cycle and cell death machinery by E2F , 2002, Nature Cell Biology.

[25]  C. Sherr.  Cancer Cell Cycles , 1996, Science.

[26]  R. Spang,et al.  Role for E2F in Control of Both DNA Replication and Mitotic Functions as Revealed from DNA Microarray Analysis , 2001, Molecular and Cellular Biology.

[27]  D. Livingston,et al.  The retinoblastoma gene product protects E2F-1 from degradation by the ubiquitin-proteasome pathway. , 1996, Genes & development.

[28]  T. Hirano,et al.  Gab-family adapter proteins act downstream of cytokine and growth factor receptors and T- and B-cell antigen receptors. , 1999, Blood.

[29]  B. Pützer,et al.  Role of the p53-homologue p73 in E2F1-induced apoptosis , 2000, Nature Genetics.

[30]  R. Bernards,et al.  Stable suppression of tumorigenicity by virus-mediated RNA interference. , 2002, Cancer cell.