Role of DOK Proteins in Lung Cancer

DOK 蛋白在肺癌中的作用

• 批准号: 7618033
• 负责人: Paul B Rothman
• 金额: $ 28.5万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7618033
• 关键词: Affect; Binding; Blast Cell; Bone Marrow Cells; Cell Lineage; Cell membrane; Cells; Chronic Myeloid Leukemia; Data; Development; Family; Family member; Frequencies; Grant; Hematopoietic; Human; Inflammatory Response; Knock-out; Knockout Mice; Lead; Lung; Lung Adenocarcinoma; Lung Inflammation; Lymphocyte; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mus; Myelogenous; Myeloproliferative disease; PH Domain; Pathway interactions; Patients; Pattern; Philadelphia Chromosome Positive Chronic Myelogenous Leukemia; Phosphotyrosine; Play; Pneumonia; Principal Investigator; Protein Family; Protein Tyrosine Kinase; Proteins; Ras Signaling Pathway; Receptor Protein-Tyrosine Kinases; Role; Signal Pathway; Squamous cell carcinoma; Stem cells; Stimulus; Structure of parenchyma of lung; Surface; Tumor Suppressor Proteins; Tyrosine; Wild Type Mouse; Work; adapter protein; base; cell growth; cell type; human stem cells; immune function; inhibitor/antagonist; lung carcinogenesis; member; overexpression; protein function; receptor; response; src Homology Region 2 Domain; stem cell population; tumor

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.

描述（由申请人提供）：Dok-1（酪氨酸激酶-1的下游）被鉴定为费城染色体阳性慢性髓性白血病（CML）患者谱系阴性原始细胞的细胞裂解物中的酪氨酸磷酸化蛋白，也是许多PTK（受体酪氨酸激酶）的主要底物。Dok家族后来扩大到7名成员，Dok-1至Dok-7。其中，Dok-1、Dok-2和Dok-3主要表达于造血系细胞。过表达数据表明，Dok蛋白可能是细胞活化的抑制剂。我们已经使用Dok-1敲除小鼠证明Dok-1是Ras途径的负调节剂，并且Dok-1和Dok-2的伴随损失导致骨髓增生性疾病，类似于小鼠中的CML。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）的小鼠的检查证实肺的自发性肺腺癌的高频率。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。对来自野生型小鼠的细支气管肺泡干细胞（BASC）的检查表明它们确实表达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。我们的资助计划确定这种对肺癌发生的抑制是否是由于BASC群体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，我们将这些数据扩展到人类，并尝试识别人类BASCs并确定它们是否表达Dok蛋白。