CITED4 inhibits hypoxia-activated transcription in cancer cells, and its cytoplasmic location in breast cancer is associated with elevated expression of tumor cell hypoxia-inducible factor 1α
CITED4 inhibits hypoxia-activated transcription in cancer cells, and its cytoplasmic location in breast cancer is associated with elevated expression of tumor cell hypoxia-inducible factor 1α
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DOI：
10.1158/0008-5472.can-04-0708
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发表时间：
2004-09-01
期刊：
影响因子：
11.2
通讯作者：
Harris, AL
中科院分区：
文献类型：
--
作者：
Fox, SB;Bragança, J;Harris, AL
缺氧诱导因子 1α 与转录共激活因子 p300/CBP 的 CH1 结构域的相互作用对于缺氧反应基因的表达和肿瘤血管生成是必需的。转录因子 CITED2 在 CH1 结构域结合 p300/CBP，并通过与缺氧诱导因子 1α 竞争，充当缺氧信号传导的负调节因子。 CITED4 是最近鉴定的 CITED 家族成员，通过 CH1 结构域结合 p300/CBP，并充当转录因子 AP-2 的共激活子。在这里，我们证明 CITED4 在体外阻断缺氧诱导因子 1α 与 p300 的结合，并抑制缺氧诱导因子 1α 反式激活和缺氧介导的报告基因激活。这些研究表明 CITED4 可能作为缺氧诱导因子 1α 的抑制剂发挥作用。为了探索 CITED4 在乳腺癌中的功能，我们测定了其在正常乳腺癌、原位乳腺癌和浸润性乳腺癌中的表达。我们还将其在 286 个浸润性乳腺肿瘤中的表达与临床病理学、缺氧标志物和生存率相关联。与正常乳腺组织中 CITED4 的核定位相反，乳腺肿瘤的特征在于细胞质和核定位。核CITED4表达与肿瘤缺氧诱导因子1α（P < 0.05）、肿瘤大小（P = 0.03）、肿瘤分级（P = 0.0001）和Chalkley血管计数（P = 0.04）呈显着负相关。 CITED4 显示与患者年龄 (P = 0.45)、雌激素受体 (P = 0.11) 或表皮生长因子受体 (P = 0.48) 没有显着相关性。这些结果表明乳腺癌发展的特点是 CITED4 的核丢失或细胞质易位，从而导致缺氧诱导因子 1α 转录拮抗剂活性的丧失。这可能是肿瘤增强缺氧诱导因子表达并导致侵袭性表型的重要机制。
The interaction of hypoxia-inducible factor 1alpha and the CH1 domain of the transcriptional coactivator p300/CBP is necessary for the expression of hypoxia responsive genes and tumor angiogenesis. The transcription factor CITED2 binds p300/CBP at the CH1 domain and functions as a negative regulator of hypoxia signaling by competing with hypoxia-inducible factor 1alpha. CITED4, a recently identified member of the CITED family, binds p300/CBP via the CH1 domain and functions as a coactivator for transcription factor AP-2. Here, we show that CITED4 blocks the binding of hypoxia-inducible factor 1alpha to p300 in vitro and inhibits hypoxia-inducible factor-1alpha transactivation and hypoxia-mediated reporter gene activation. These studies suggest that CITED4 might function as an inhibitor of hypoxia-inducible factor 1alpha. To explore the function of CITED4 in breast cancer, we determined its expression in normal, in situ and invasive breast cancers. We also correlated its expression in 286 invasive breast tumors with clinicopathological, hypoxia markers and survival. In contrast to the nuclear localization of CITED4 in normal breast tissue, breast tumors were characterized by cytoplasmic and nuclear localization. Nuclear CITED4 expression was significantly inversely associated with tumor hypoxia-inducible factor 1alpha (P < 0.05), tumor size (P = 0.03), tumor grade (P = 0.0001), and Chalkley vessel count (P = 0.04). CITED4 showed no significant correlation with patient age (P = 0.45), estrogen receptor (P = 0.11), or epidermal growth factor receptor (P = 0.48). These results show that breast cancer development is characterized by either nuclear loss or cytoplasmic translocation of CITED4, with consequent loss of hypoxia-inducible factor-1alpha transcriptional antagonist activity. This may be an important mechanism by which tumors enhance hypoxia-inducible factor expression and result in an aggressive phenotype.