Kritikou Ekaterini A, Sharkey Andrew, Abell Kathrine, Came Paul J, Anderson Elizabeth, Clarkson Richard W E, Watson Christine J
Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK.
Development. 2003 Aug;130(15):3459-68. doi: 10.1242/dev.00578.
STAT3 is the key mediator of apoptosis in mammary gland. We demonstrate here that LIF is the physiological activator of STAT3, because in involuting mammary glands of Lif(-/-) mice, pSTAT3 is absent and the STAT3 target, C/EBPdelta, is not upregulated. Similar to Stat3 knockouts, Lif(-/-) mammary glands exhibit delayed involution, reduced apoptosis and elevated levels of p53. Significantly, Lif(-/-) glands display precocious development during pregnancy, when pSTAT3 is not normally detected. We show that pERK1/2 is significantly reduced in Lif(-/-) glands at this time, suggesting that at this stage LIF mediates its effects through pERK1/2. Inhibition of LIF-mediated ERK1/2 phosphorylation potentiates the proapoptotic effects of STAT3. LIF therefore signals alternately through ERK1/2, then STAT3, to regulate mammary growth and apoptosis.
信号转导和转录激活因子3（STAT3）是乳腺细胞凋亡的关键调节因子。我们在此证明，白血病抑制因子（LIF）是STAT3的生理激活剂，因为在Lif基因敲除小鼠的退化乳腺中，磷酸化STAT3（pSTAT3）缺失，且STAT3的靶标C/EBPδ未上调。与Stat3基因敲除小鼠相似，Lif基因敲除小鼠的乳腺表现出退化延迟、细胞凋亡减少和p53水平升高。值得注意的是，在正常情况下检测不到pSTAT3的孕期，Lif基因敲除小鼠的乳腺表现出早熟发育。我们发现此时Lif基因敲除小鼠乳腺中的磷酸化细胞外信号调节激酶1/2（pERK1/2）显著减少，这表明在此阶段LIF通过pERK1/2介导其作用。抑制LIF介导的ERK1/2磷酸化可增强STAT3的促凋亡作用。因此，LIF通过ERK1/2和STAT3交替发出信号，以调节乳腺的生长和细胞凋亡。
