RESUMO
Although C1D has been shown to be involved in DNA double-strand break repair, how C1D expression was induced and the mechanism(s) by which C1D facilitates DNA repair in mammalian cells remain poorly understood. We and others have previously shown that expression of xeroderma pigmentosum B (XPB) protein efficiently compensated the UV irradiation-sensitive phenotype of 27-1 cells, which lack functional XPB. To further explore XPB-regulated genes that could be involved in UV-induced DNA repair, differential display analysis of mRNA levels from CHO-9, 27-1, and 27-1 complemented with wild-type XPB was done and C1D gene was identified as one of the major genes whose expression was significantly upregulated by restoring XPB function. We found that XPB is essential to induce C1D transcription after UV irradiation. The increase in C1D expression effectively compensates for the UV-induced proteolysis of C1D and thus maintains cellular C1D level to cope with DNA damage inflicted by UV irradiation. We further showed that although insufficient to rescue 27-1 cells from UV-induced apoptosis by itself, C1D facilitates XPB DNA repair through direct interaction with XPB. Our findings provided direct evidence that C1D is associated with DNA repair complex and may promote repair of UV-induced DNA damage.
Assuntos
Proteínas Reguladoras de Apoptose/fisiologia , Apoptose/genética , Proteínas Correpressoras/biossíntese , Dano ao DNA/genética , DNA Helicases/fisiologia , Reparo do DNA/genética , Proteínas de Ligação a DNA/fisiologia , Raios Ultravioleta , Animais , Apoptose/efeitos da radiação , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/efeitos da radiação , Células CHO , Proteínas Correpressoras/genética , Proteínas Correpressoras/efeitos da radiação , Cricetinae , Cricetulus , Dano ao DNA/efeitos da radiação , DNA Helicases/genética , DNA Helicases/efeitos da radiação , Reparo do DNA/efeitos da radiação , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/efeitos da radiação , Humanos , Ativação Transcricional/genética , Ativação Transcricional/efeitos da radiação , Regulação para Cima/genética , Regulação para Cima/efeitos da radiaçãoRESUMO
Vascular endothelial growth factor (VEGF)-VEGF receptor (VEGFR) system has been shown to play central roles not only in physiological angiogenesis, but also in pathological angiogenesis in diseases such as cancer. Based on these findings, a variety of anti-angiogenic drugs, including anti-VEGF antibodies and VEGFR/multi-receptor kinase inhibitors have been developed and approved for the clinical use. While the clinical efficacy of these drugs has been clearly demonstrated in cancer patients, they have not been shown to be effective in curing cancer, suggesting that further improvement in their design is necessary. Abnormal expression of an endogenous VEGF-inhibitor sFlt-1 has been shown to be involved in a variety of diseases, such as preeclampsia and aged macular degeneration. In addition, various factors modulating angiogenic processes have been recently isolated. Given this complexity then, extensive studies on the interrelationship between VEGF signals and other angiogenesis-regulatory systems will be important for developing future strategies to suppress diseases with an angiogenic component.
Assuntos
Humanos , Inibidores da Angiogênese , Anticorpos , Degeneração Macular , Neovascularização Patológica , Neovascularização Fisiológica , Fosfotransferases , Pré-Eclâmpsia , Receptores de Fatores de Crescimento do Endotélio Vascular , Fator A de Crescimento do Endotélio VascularRESUMO
Vascular endothelial growth factor (VEGF)-VEGF receptor (VEGFR) system has been shown to play central roles not only in physiological angiogenesis, but also in pathological angiogenesis in diseases such as cancer. Based on these findings, a variety of anti-angiogenic drugs, including anti-VEGF antibodies and VEGFR/multi-receptor kinase inhibitors have been developed and approved for the clinical use. While the clinical efficacy of these drugs has been clearly demonstrated in cancer patients, they have not been shown to be effective in curing cancer, suggesting that further improvement in their design is necessary. Abnormal expression of an endogenous VEGF-inhibitor sFlt-1 has been shown to be involved in a variety of diseases, such as preeclampsia and aged macular degeneration. In addition, various factors modulating angiogenic processes have been recently isolated. Given this complexity then, extensive studies on the interrelationship between VEGF signals and other angiogenesis-regulatory systems will be important for developing future strategies to suppress diseases with an angiogenic component.