title: KSHV viral cyclin interferes with T-cell development and induces lymphoma through Cdk6 and Notch activation in vivo.
abstract: Kaposi's sarcoma herpesvirus (KSHV)-encoded v-cyclin, a homolog of cellular cyclin D2, activates cellular CDK6, promotes G1-S transition of the cell cycle, induces DNA damage, apoptosis, autophagy and is reported to have oncogenic potential. Here we show that in vivo expression of v-cyclin in the B- and T-cell lymphocyte compartments results in a markedly low survival due to high penetrance of early-onset T-cell lymphoma and pancarditis. The v-cyclin transgenic mice have smaller pre-tumorigenic lymphoid organs, showing decreased cellularity, and increased proliferation and apoptosis. Furthermore, v-cyclin expression resulted in decreased amounts of CD3-expressing mature T-cells in the secondary lymphoid organs concurrent with alterations in the T-cell subpopulations of the thymus. This suggests that v-cyclin interferes with normal T-cell development. As the Notch pathway is recognized for its role in both T-cell development and lymphoma initiation, we addressed the role of Notch in the v-cyclin-induced alterations. Fittingly, we demonstrate induction of Notch3 and Hes1 in the pre-tumorigenic thymi and lymphomas of v-cyclin expressing mice, and show that lymphoma growth and viability are dependent on activated Notch signaling. Notch3 transcription and growth of the lymphomas was dependent on CDK6, as determined by silencing of CDK6 expression or chemical inhibition, respectively. Our work here reveals a viral cyclin-CDK6 complex as an upstream regulator of Notch receptor, suggesting that cyclins can play a role in the initiation of Notch-dependent lymphomagenesis.
authors.affiliation: a Institute of Biotechnology ; University of Helsinki ; Helsinki , Finland.
authors.forename: Pirita
authors.initials: P
authors.lastname: Pekkonen
authors.forename: Annika
authors.initials: A
authors.lastname: Järviluoma
authors.forename: Nadezhda
authors.initials: N
authors.lastname: Zinovkina
authors.forename: Anna
authors.initials: A
authors.lastname: Cvrljevic
authors.forename: Sonam
authors.initials: S
authors.lastname: Prakash
authors.forename: Jukka
authors.initials: J
authors.lastname: Westermarck
authors.forename: Gerard I
authors.initials: GI
authors.lastname: Evan
authors.forename: Ethel
authors.initials: E
authors.lastname: Cesarman
authors.forename: Emmy W
authors.initials: EW
authors.lastname: Verschuren
authors.forename: Päivi M
authors.initials: PM
authors.lastname: Ojala
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism*; D057809:HEK293 Cells; D019288:Herpesvirus 8, Human / Q000378:metabolism*; D006801:Humans; D016399:Lymphoma, T-Cell / Q000378:metabolism* / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism* / Q000821:virology
chemical_list: C499373:Notch3 protein, mouse; D000071656:Receptor, Notch3; D051880:Receptors, Notch; C495912:Cdk6 protein, mouse; D051361:Cyclin-Dependent Kinase 6
keywords: Cdk6; Cdk6, cyclin dependent kinase 6; GSI, γ-secretase inhibitor; KS, Kaposi's sarcoma; KSHV; KSHV, Kaposi's sarcoma herpesvirus; NICD1, Notch1 intracellular domain; NICD3, Notch3 intracellular domain; Notch; PEL, primary effusion lymphoma; PI, propidium iodide; T-cell lymphoma; v-cyclin; v-cyclin, viral cyclin