Studies on the function of LKB I /STK II, a Ser/Thr kinase mutated in Peutz-Jeghers syndrome

黑斑息肉综合征是一种常染色体显性遗传病。Peuts-Jegehers综合征的早期表现包括嘴唇的黑色素细胞斑点和胃肠道多发性错构瘤性息肉。在晚年，Peuts-Jeghers综合征患者在各种组织中的癌症发病率显著增加。我们对黑斑息肉综合征中突变的丝氨酸/苏氨酸蛋白激酶LKB1/STK11的机制和功能进行了研究，并取得了以下发现。1)以LKB/STK11为诱饵进行酵母双杂交筛选，确定LMO转录因子家族为LKB1/STK11的合作伙伴。2)LMO转录因子家族与GATA相互作用并激活其活性。3)LMO家族转录因子与P53协同激活CDK抑制因子p21的表达。LDB1和GATA6也参与了LMO家族介导的p21反式激活。4)LKB1/STK11在Hela细胞和G361细胞中的过表达导致细胞周期G1期停滞。5)到目前为止，我们还没有成功鉴定出LKB1/STK11磷酸化的底物蛋白。

Peutz-Jeghers syndrome is an autosomal dominant disease. Early manifestations of Peuts-Jegehers syndrome include melanocytic macules of the lips and multiple hamartomatous polyps in the gastrointestinal tract. Later in life, Peuts-Jeghers syndrome patients have a dramatically increased incidence of cancers in a wide variety of tissues. We investigated the mechanism and function of LKB1/STK11, a Ser/Thr kinase mutated in Peutz-Jehgers syndrome, and made the following findings. 1) We performed a yeast two-hybrid screen using LKB/STK11 as bait, and identified the LMO family of transcription factors as partners for LKB1/STK11. 2) The LMO family of transcription factors interacts with GATA and activates its activity. 3) In cooperation with p53, the LMO family of transcription factors activates the expression of CDK inhibitor p21. Ldb1 and GATA6 were also found to participate in the LMO family-mediated transactivation of p21. 4) Overexpression of LKB1/STK11 in Hela cells as well as in G361 cells resulted in the G1 arrest of the cell cycle. 5) So far we have not succeeded to identify substrate proteins for phosphorylation by LKB1/STK11.