Altered Proteoglycan Gene Expression and Cancer

描述(申请人提供)：本提案的长期目标是阐明核心蛋白聚糖在控制细胞增殖中的作用机制。核心假设是核心蛋白聚糖是癌症生长的天然拮抗剂，这是一个基于几个关键观察结果的工作理论：[A]核心蛋白聚糖在大多数转化细胞中受到抑制，但在静止细胞中显著增加。[B]有针对性地破坏核心蛋白聚糖和p53基因的动物很快就会死于胸腺淋巴瘤，这表明核心蛋白蛋白的缺乏可能导致肿瘤的发生。[C]异位表达Decorin可在多种转化细胞中诱导深刻的细胞抑制效应。[D]核心蛋白聚糖与表皮生长因子受体(EGFR)相互作用，导致其酪氨酸激酶活性显著减弱，从而导致生长抑制。 在接下来的五年里，我们计划继续对哺乳动物核心蛋白聚糖的生物学研究，并破译核心蛋白聚糖发挥细胞抑制功能的分子机制。具体地说，我们计划：(1)破译核心蛋白聚糖抑制EGFR活性的作用机制。(2)确定Decorin/EGFR相互作用的精确结构要求；(3)研究Decorin作为抗肿瘤因子的体内功能。 这些协调一致的研究路线应该坚定地确立核心蛋白在肿瘤发生中的功能作用，并阐明其作用机制。核心蛋白聚糖是EGFR的一种新的生物配基，这种相互作用导致EGFR激酶和信号的明显减弱，这一发现首次证明了分泌的蛋白多糖与这一重要的信号转导途径相互作用。预期的结果可能为基础癌症研究开辟新的视角，并可能导致未来针对促进这种蛋白多糖表达的癌症预防和治疗方法，从而增加一种天然的肿瘤细胞生长抑制物。

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to elucidate the mechanism of action of decorin in controlling cell proliferation. The central hypothesis is that decorin is a natural antagonist of cancer growth, a working theory based on several key observations: [a] Decorin levels are suppressed in most transformed cells, but markedly increased in quiescent cells. [b] Animals harboring a targeted disruption of decorin and p53 genes die rapidly of thymic lymphomas, indicating that lack of decorin is permissive for tumorigenesis. [c] Ectopic expression of decorin induces profound cytostatic effects in a wide variety of transformed cells. [d] Decorin interacts with the epidermal growth factor receptor (EGFR) and causes a profound attenuation of its tyrosine kinase activity, thereby leading to growth inhibition. Over the next five years we plan to continue the studies on the biology of mammalian decorin and decode the molecular mechanisms through which decorin exerts its cytostatic functions. Specifically, we plan to: (1) Decipher the mechanism of action of decorin in suppressing EGFR activity. (2) Determine the precise structural requirements for decorin/EGFR interaction, and (3) Investigate the in vivo function of decorin as an anti-oncogenic factor. These concerted research lines should firmly establish the functional roles of decorin in tumorigenicity and shed light on its mechanism of action. The discovery that decorin is a novel biological ligand for the EGFR and that this interaction leads to an overt attenuation of the EGFR kinase and signaling provides the first demonstration of a secreted proteoglycan interacting with this important signal transducing pathway. The expected results could open novel perspectives for basic cancer research, and could lead to future approaches of cancer prevention and treatment directed at boosting the expression of this proteoglycan, thereby increasing a natural inhibitor of tumor cell growth.