TY - JOUR
T1 - Up-regulation of Bcl-2 Homology 3 (BH3)-only Proteins by E2F1 Mediates Apoptosis
AU - Hershko, Tzippi
AU - Ginsberg, Doron
PY - 2004/3/5
Y1 - 2004/3/5
N2 - The E2F1 transcription factor is a critical down-stream target of the tumor suppressor pRB. The retinoblastoma (RB) pathway is often inactivated in human tumors, resulting in deregulated E2F activity that can induce both proliferation and apoptosis. Bcl-2 homology 3 (BH3)-only proteins are pro-apoptotic members of the Bcl-2 protein family that trigger apoptosis in response to diverse stimuli. We show here that E2F1 up-regulates the expression of the pro-apoptotic BH3-only proteins PUMA, Noxa, Bim, and Hrk/DP5 through a direct transcriptional mechanism. Expression of the E7 protein of HPV16, which disrupts RB/E2F complexes, also up-regulates the expression of these four BH3-only proteins, implicating endogenous E2F in this phenomenon. Indeed, endogenous E2F1 binds the promoters of these four genes. Furthermore, inhibition of E2F1-induced expression of either Noxa or PUMA results in a significant reduction in E2F1-induced apoptosis, indicating that increased Noxa and PUMA levels mediate this E2F1-induced apoptosis. Importantly, inhibition of E2F activity abolishes DNA damage-induced elevation of PUMA levels, implicating E2F in the physiological regulation of PUMA expression. These data provide a novel direct link between E2F and the apoptotic machinery and may explain the increased sensitivity of cells with a defective RB/E2F pathway to chemotherapy.
AB - The E2F1 transcription factor is a critical down-stream target of the tumor suppressor pRB. The retinoblastoma (RB) pathway is often inactivated in human tumors, resulting in deregulated E2F activity that can induce both proliferation and apoptosis. Bcl-2 homology 3 (BH3)-only proteins are pro-apoptotic members of the Bcl-2 protein family that trigger apoptosis in response to diverse stimuli. We show here that E2F1 up-regulates the expression of the pro-apoptotic BH3-only proteins PUMA, Noxa, Bim, and Hrk/DP5 through a direct transcriptional mechanism. Expression of the E7 protein of HPV16, which disrupts RB/E2F complexes, also up-regulates the expression of these four BH3-only proteins, implicating endogenous E2F in this phenomenon. Indeed, endogenous E2F1 binds the promoters of these four genes. Furthermore, inhibition of E2F1-induced expression of either Noxa or PUMA results in a significant reduction in E2F1-induced apoptosis, indicating that increased Noxa and PUMA levels mediate this E2F1-induced apoptosis. Importantly, inhibition of E2F activity abolishes DNA damage-induced elevation of PUMA levels, implicating E2F in the physiological regulation of PUMA expression. These data provide a novel direct link between E2F and the apoptotic machinery and may explain the increased sensitivity of cells with a defective RB/E2F pathway to chemotherapy.
UR - http://www.scopus.com/inward/record.url?scp=1542305653&partnerID=8YFLogxK
U2 - 10.1074/jbc.M312866200
DO - 10.1074/jbc.M312866200
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C2 - 14684737
AN - SCOPUS:1542305653
SN - 0021-9258
VL - 279
SP - 8627
EP - 8634
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 10
ER -