Tumour suppressor networks: the role of SHIP-1 and Lyn in suppressing haematopoietic tumours

每年有大量的澳大利亚人死于造血恶性肿瘤。提高我们对这些疾病背后的分子机制的理解对于设计更有效的治疗方法至关重要。Lyn和SHIP-1是在血细胞中发现的酶，它们都参与终止细胞反应。因此，这些酶对于维持免疫系统的稳定性至关重要。虽然这些酶具有独特的作用，但我们也有充分的证据表明，在某些情况下，Lyn和SHIP-1参与相同的生化途径。我们培育出了不能制造Lyn蛋白的老鼠，并发现这些老鼠会产生血细胞肿瘤。缺乏SHIP-1的小鼠会出现许多血液学缺陷，但会在年轻时因肺部炎症而死亡，这使得评估SHIP-1在年龄依赖性肿瘤发展中的作用变得困难。我们现在希望通过产生在特定白细胞区室中缺乏SHIP-1的小鼠来研究SHIP-1在肿瘤发展中的作用。我们也在研究SHIP-1和Lyn如何协同抑制肿瘤，我们最近培育了同时缺乏SHIP-1和Lyn的小鼠。初步研究表明，复合突变小鼠可发生多种血液学恶性肿瘤。我们将在这些动物中充分表征肿瘤的发展，并确定这种病理的分子基础。我们将重点关注先前与肿瘤发生有关的两种途径。这些研究将提高我们对Lyn和SHIP-1如何在血细胞发育、细胞稳态和肿瘤发生中合作的认识，并增加我们对肿瘤抑制网络的生物学和生化理解。

Haematopoietic malignancies kill a large number of Australians each year. Improving our understanding of the molecular mechanisms that underlie these diseases is essential for the design of more effective treatments. Lyn and SHIP-1 are enzymes that are found in blood cells, and both participate in terminating cellular responses. As such, these enzymes are critically important for maintaining stability in the immune system. While these enzymes have unique roles, we also have good evidence that in some instances Lyn and SHIP-1 participate in the same biochemical pathway. We have created mice that are unable to make Lyn protein, and have found that these mice develop blood cell tumours. Mice lacking SHIP-1 develop a number of haematological defects, but die at a young age due to an inflammatory lung condition, making an assessment of the role of SHIP-1 in age-dependent tumour development difficult. We now wish to study the role of SHIP-1 in tumour development, by generating mice that lack SHIP-1 in specific white blood cell compartments. We are also investigating how SHIP-1 and Lyn cooperate in tumour suppression, and we have recently generated mice that simultaneously lack both SHIP-1 and Lyn. Preliminary studies indicate that compound mutant mice develop multiple haematological malignancies. We will fully characterize tumour development in these animals, and determine the molecular basis for this pathology. We will focus on two pathways that have been previously implicated in oncogenesis. These studies will improve our insight into how Lyn and SHIP-1 cooperate in blood cell development, cellular homeostasis and oncogenesis, and add to our biological and biochemical understanding of tumour suppressor networks.