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Regulation of G1 Cell Cycle Progression

Anil Narasimha

Appointment Period: 2011-2013, Grant Years: [27,28]

Anil NarasimhaDeregulation of G1 cell cycle progression is thought to occur in the vast majority of human malignancies. The Retinoblastoma tumor suppressor gene (Rb) is a master regulator of G1 cell cycle progression, the DNA damage response and differentiation. However, the Rb gene is infrequently mutated in cancer; instead upstream regulators, including the p16 tumor suppressor gene and cyclin D1/2/3:Cdk4/6 genes, are altered in the majority of human malignancies resulting in upregulation of Cyclin D:Cdk4/6 activity. Rb contains 15 Cdk phosphorylation sites and is thought to exist in three general isoforms: un-phosphorylated Rb, hypo-phosphorylated Rb, and inactive hyper-phosphorylated Rb. To account for the lack of Rb mutations, a large body of work has led to a widely accepted model of G1 cell cycle progression that proposes cyclin D:Cdk4/6 inactivates Rb during early G1 phase by progressive multi-phosphorylation or hypo-phosphorylation to release E2F transcription factors, resulting in the activation of cyclin E:Cdk2 and Rb hyper-phosphorylation. However, due to the use of supra-physiologic overexpression studies, this model remains largely unproven and the biologically active isoform of Rb remains unknown. Using highly synchronized primary and tumorigenic cells, performing biochemistry on physiologic levels and activities of proteins, and developing 2D isoelectric focusing of Rb, my work has determined that Rb is exclusively mono-phosphorylated during early G1 phase by cyclin D:Cdk4/6 complexes. Mono-phosphorylated Rb functioned to induce a G1 arrest, bind E2F transcription factors and regulate the global transcriptional profile, whereas non-phosphorylatable RbDCdk was non-functional, showing that mono-phosphorylated Rb is the biologically active isoform of Rb. My observations fundamentally change our understanding of G1 cell cycle regulation and show that cyclin D:Cdk4/6 complexes activate Rb by monophosphorylation during early G1 phase. Importantly, these observations point to the activation of cyclin E:Cdk2 complexes as a likely key oncogenic step in the progression of cancer.

PUBLICATIONS (resulting from this training)

Narasimha, A.M. Shi, W. & Dowdy, S.F. Cell Cycle Controls in G1 and G0. Encyclop. Biol. Chem. (in press)(2012).

Narasimha, A.M., Shapiro, G.S., Hagopian, J.C., Liang, J., Albuquerque, C.P., Zhou, H. & Dowdy, S.F. Exclusive Activation of Rb by Mono-Phosphorylation During Early G1 Phase. (submitted).

Narasimha AN, Dowdy SF. Treating Cancer by RNAi Therapeutics: Targeting G1 Cell Cycle Regulation. (2012) Invited chapter, in preparation.