CREB-binding protein regulates apoptosis and growth of HMECs grown in reconstituted ECM via laminin-5
CREB-binding protein regulates apoptosis and growth of HMECs grown in reconstituted ECM via laminin-5
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DOI：
10.1242/jcs.02616
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发表时间：
2005-11-01
影响因子：
4
通讯作者：
Seewaldt, VL
中科院分区：
文献类型：
--
作者：
Dietze, EC;Bowie, ML;Seewaldt, VL
正常乳腺上皮细胞和细胞外基质（ECM）之间的相互作用对乳腺稳态非常重要。ECM和正常乳腺上皮细胞之间相互作用的丧失被认为是乳腺癌发生的早期事件。CREB结合蛋白（CBP）是细胞增殖和凋亡的重要调节因子，但CBP在ECM信号传导中的作用尚不清楚。CBP在基底细胞角蛋白阳性的HMEC中受到抑制（CK 5/6（+）、CK 14（+）、CK 8（-）、CK 18（-）、CK 19（-））。CBP的抑制导致重建的ECM介导的生长控制和细胞凋亡的损失和层粘连蛋白-5 α 3-链表达的损失。正常人乳腺上皮细胞（HMEC）中CBP的抑制导致CBP占据LAMA 3A启动子的丢失，LAMA 3A启动子活性和层粘连蛋白-5 α 3链表达降低。CBP在已失去重建ECM介导的生长调节和凋亡的CBP阴性HMEC中的外源性表达导致（1）CBP占据LAMA 3A启动子，（2）LAMA 3A活性和层粘连蛋白-5 W-链表达增加，以及（3）重建ECM介导的生长调节和凋亡增强。同样，抑制层粘连蛋白-5 α 3-链在HMEC中的表达导致重建ECM介导的生长控制和凋亡的丧失。这些观察结果表明，在基底细胞角蛋白阳性HMEC中CBP的丢失导致重建ECM介导的生长控制的丢失，并通过LAMA 3A活性和层粘连蛋白-5 α 3链表达的丢失导致细胞凋亡。这些研究的结果可能为基底型乳腺癌发生的早期事件提供深入的了解。
Interactions between normal mammary epithelial cells and extracellular matrix (ECM) are important for mammary gland homeostasis. Loss of interactions between ECM and normal mammary epithelial cells are thought to be an early event in mammary carcinogenesis. CREB-binding protein (CBP) is an important regulator of proliferation and apoptosis but the role of CBP in ECM signaling is poorly characterized. CBP was suppressed in basal-cytokeratin-positive HMECs (CK5/6(+), CK14(+), CK8(-), CK18(-), CK19(-)). Suppression of CBP resulted in loss of reconstituted ECM-mediated growth control and apoptosis and loss of laminin-5 alpha 3-chain expression. Suppression of CBP in normal human mammary epithelial cells (HMECs) resulted in loss of CBP occupancy of the LAMA3A promoter and decreased LAMA3A promoter activity and laminin-5 alpha 3 chain expression. Exogenous expression of CBP in CBP-negative HMECs that have lost reconstituted ECM-mediated growth regulation and apoptosis resulted in (1) CBP occupancy of the LAMA3A promoter, (2) increased LAMA3A activity and laminin-5 W-chain expression, and (3) enhancement of reconstituted ECM-mediated growth regulation and apoptosis. Similarly, suppression of laminin-5 alpha 3-chain expression in HMECs resulted in loss of reconstituted ECM-mediated growth control and apoptosis. These observations suggest that loss of CBP in basal-cytokeratin-positive HMECs results in loss of reconstituted ECM-mediated growth control and apoptosis through loss of LAMA3A activity and laminin-5 alpha 3-chain expression. Results in these studies may provide insight into early events in basal-type mammary carcinogenesis.