Noninvasive assessment of E2F-1-mediated transcriptional regulation in vivo.
Cancer Res
; 68(14): 5932-40, 2008 Jul 15.
Article
en En
| MEDLINE
| ID: mdl-18632648
ABSTRACT
Targeted therapies directed against individual cancer-specific molecular alterations offer the development of disease-specific and individualized treatment strategies. Activation of the transcription factor E2F-1 via alteration of the p16-cyclinD-Rb pathway is one of the key molecular events in the development of gliomas. E2F-1 binds to and activates the E2F-1 promoter in an autoregulatory manner. The human E2F-1 promoter has been shown to be selectively activated in tumor cells with a defect in the pRb pathway. Paradoxically, E2F-1 also carries tumor suppressor function. Our investigations focused on analyzing the dynamics of the activity of the E2F-1 responsive element under basal conditions and certain stimuli such as chemotherapy using molecular imaging technology. We constructed a retrovirus bearing the Cis-E2F-TA-LITG reporter system to noninvasively assess E2F-1-dependent transcriptional regulation in culture and in vivo. We show that our reporter system is sensitive to monitor various changes in cellular E2F-1 levels and its transcriptional control of our reporter system to follow the state of the Rb/E2F pathway and the DNA damage-induced up-regulation of E2F-1 activity in vivo. Exposure to 1,3-bis(2-chloroethyl)-1-nitrosourea leads to increased E2F-1 expression levels in a dose- and time-dependent manner, which can be quantified by imaging in vivo, leading to an alteration of cell cycle progression and caspase 3/7 activity. In summary, noninvasive imaging of E2F-1 as a common downstream regulator of cell cycle progression using the Cis-E2F-TA-LUC-IRES-TKGFP reporter system is highly attractive for evaluating the kinetics of cell cycle regulation and the effects of novel cell cycle targeting anticancer agents in vivo.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Transcripción Genética
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Neoplasias Encefálicas
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Regulación Neoplásica de la Expresión Génica
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Factor de Transcripción E2F1
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Glioma
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Microscopía Fluorescente
Límite:
Animals
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Humans
Idioma:
En
Revista:
Cancer Res
Año:
2008
Tipo del documento:
Article
País de afiliación:
Alemania