RESUMEN
Cyclin-Dependent Kinase 9 (CDK9) is part of a functional diverse group of enzymes responsible for cell cycle control and progression. It associates mainly with Cyclin T1 and forms the Positive Transcription Elongation Factor b (p-TEFb) complex responsible for regulation of transcription elongation and mRNA maturation. Recent studies have highlighted the importance of CDK9 in many relevant pathologic processes, like cancer, cardiovascular diseases, and viral replication. Herein we provide an overview of the different pathways in which CDK9 is directly and indirectly involved.
Asunto(s)
Enfermedades Cardiovasculares/metabolismo , Quinasa 9 Dependiente de la Ciclina/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias/metabolismo , Virosis/metabolismo , Animales , Enfermedades Cardiovasculares/genética , Ciclina T/genética , Ciclina T/metabolismo , Quinasa 9 Dependiente de la Ciclina/genética , Humanos , Proteínas de Neoplasias/genética , Neoplasias/genética , Factor B de Elongación Transcripcional Positiva/genética , Factor B de Elongación Transcripcional Positiva/metabolismo , Elongación de la Transcripción Genética , Virosis/genéticaRESUMEN
HIV-1 latency is a major obstacle to HIV-1 eradication. Coinfection with HTLV-1 has been associated with faster progression to AIDS. HTLV-1 encodes the transactivator Tax which can activate both HTLV-1 and HIV-1 transcription. Here, we demonstrate that Tax activates HIV transcription in latent CD4+ T cells. Tax promotes the activation of P-TEFb, releasing CDK9 and Cyclin T1 from inactive forms, promoting transcription elongation and reactivation of latent HIV-1. Tax mutants lacking interaction with the HIV-1-LTR promoter were not able to activate P-TEFb, with no subsequent activation of latent HIV. In HIV-infected primary resting CD4+ T cells, Tax-1 reactivated HIV-1 transcription up to five fold, confirming these findings in an ex vivo latency model. Finally, our results confirms that HTLV-1/Tax hijacks cellular partners, promoting HIV-1 transcription, and this interaction should be further investigated in HIV-1 latency studies in patients with HIV/HTLV-1 co-infection.
Asunto(s)
Linfocitos T CD4-Positivos/virología , Productos del Gen tax/genética , VIH-1/genética , Virus Linfotrópico T Tipo 1 Humano/genética , Transcripción Genética/genética , Activación Transcripcional/genética , Línea Celular Tumoral , Coinfección , Ciclina T/metabolismo , Quinasa 9 Dependiente de la Ciclina/metabolismo , Proteínas Fluorescentes Verdes/genética , Humanos , Células Jurkat , Factor B de Elongación Transcripcional Positiva/metabolismo , Regiones Promotoras Genéticas/genética , Latencia del Virus/genéticaRESUMEN
Human PTE Fb is a protein kinase composed by CDK9 and Cyclin T that controls the elongation phase of RNA Pol II. This complex also affects the activation and differentiation program of lymphoid cells. In this study we found that several head and neck tumor cell lines overexpress PTE Fb. We also established that Cyclin T1 is able to induce transformation in vitro, as we determined by foci and colony formation assays. Nu/nu mice s.c. injected with stable transfected Cyclin T1 cells (NIH 3T3 Cyclin T1) developed tumors faster than animals injected with control cells (NIH 3T3 beta-gal). In vitro, NIH 3T3 Cyclin T1 cells show increased proliferation and CDK4-Rb phosphorylation. Even more, silencing E2F1 expression (shRNA E2F1) in NIH 3T3 cells resulted in a dramatic inhibition of Cyclin T1-induced foci. All these data demonstrate for the first time the Cyclin T1 oncogenic function and suggest a role for this protein in controlling cell cycle probably via Rb/E2F1 pathway.