Role of DOK Proteins in Lung Cancer

描述（由申请人提供）：Dok-1（酪氨酸激酶-1的下游）在费城染色体阳性慢性髓性白血病（CML）患者的谱系阴性母细胞裂解物中被鉴定为酪氨酸磷酸化蛋白，也是许多PTKs（受体酪氨酸激酶）的主要底物。从那以后，德家族扩大到7个成员，从Dok-1到Dok-7。在7个成员中，Dok-1、Dok-2和Dok-3主要在造血系细胞中表达。过表达数据表明，Dok蛋白可能是细胞活化的抑制剂。我们利用敲除Dok-1的小鼠证明了Dok-1是Ras通路的负调节因子，并且Dok-1和Dok-2的同时缺失会导致类似于小鼠CML的骨髓增生性疾病。虽然Dok在几种癌症中起作用，但它在肺癌中的作用以前没有被描述过。对缺乏Dok-1、Dok-2和Dok-3 （TKO）的小鼠的检查显示，自发性肺腺癌的发生频率很高。在肺癌发生之前，小鼠也会发生以淋巴细胞为主的自发性肺部炎症。野生型小鼠细支气管肺泡干细胞（BASCs）的检测表明，它们确实表达Dok-1、Dok-2和Dok-3。这些数据使我们假设Dok蛋白是肺癌的抑制因子。我们的拨款旨在确定这种对肺癌发生的抑制是否由于BASC种群的变化以及在这些小鼠中观察到的肺部炎症是否起作用。此外，我们将把这些数据扩展到人类，并试图鉴定人类basc并确定它们是否表达Dok蛋白。

DESCRIPTION (provided by applicant): Dok-1 (for downstream of tyrosine kinase-1) was identified as a tyrosine phosphorylated protein in the cell lysates of lineage negative blasts from Philadelphia chromosome positive chronic myelogenous leukemia (CML) patients and as well as a major substrate of many PTKs (receptor tyrosine kinases). The Dok family has since been expanded to seven members, Dok-1 to Dok-7. Among seven members, Dok-1, Dok-2 and Dok-3 are mainly expressed in hematopoietic lineage cells. Overexpression data suggests that the Dok proteins may be inhibitors of cellular activation. We have shown that Dok-1 is negative regulator of Ras pathway using Dok-1 knock out mouse and that concomitant loss of Dok-1 and Dok-2 results in a myeloproliferative disease, similar to CML in mice. Although Dok has been implicated in playing a role in several cancers, its role in lung cancer has not previously been described. Examination of mice lacking Dok-1, Dok-2 and Dok-3 (TKO) demonstrate a high frequency of spontaneous lung adenocarcinoma of the lung. Prior to the development of lung cancer, mice also develop spontaneous lung inflammation with a predominance of lymphocytes. Examination of bronchioalveolar stem cells (BASCs) from wild type mice demonstrates that they do express Dok-1, Dok-2 and Dok-3. These data lead us to hypothesize that Dok proteins are suppressors of lung cancer. Our grant proposes to determine if this suppression of lung carcinogenesis is due to changes in the BASC population and whether the lung inflammation observed in these mice plays a role. In addition, we will extend these data to humans and attempt to identify human BASCs and determine if they express Dok proteins.