Role of the signal transducer and activator of transcription-3 in epithelial cell differentiation

动物体内的细胞经常停止分裂，变成专门的细胞和组织。这个基本过程被称为“分化”。如果分化受到干扰，那么细胞可能会不受控制地分裂，导致各种疾病。

Cells in the body of an animal often stop dividing and change into specialised cells and tissues. This fundamental process is called "differentiation". If differentiation is disturbed, then the cells may divide uncontrollably and cause a variety of diseases. We are proposing to study the mechanism of differentiation of breast epithelial cells, which normally produce milk. We will use as model the cultured cell line HC11 which is able to multiply as well as differentiate in a petri dish, under the appropriate conditions. HC11 cells are derived from the epithelial cells that line the ducts of the breast, and behave in culture in a manner that resembles their behaviour in the animal; if prolactin, the lactation hormone, is added to the growth medium, then HC11 cells produce milk proteins, that is they are converted into milk-producing cells. For differentiation to occur, HC11 cells must adhere to one another. This happens through proteins on the cell surface called "cadherins" that stick to each other like “velcro”. Interestingly, our lab recently demonstrated that besides this structural role, cadherins also activate a protein called "Stat3". Since cell to cell adhesion is required for differentiation, which would activate Stat3, we are proposing to examine the role of the cadherin/Stat3 pathway upon the differentiation of HC11 cells. Our preliminary results demonstrated that inhibition of Stat3 with a drug prevents differentiation of HC11 cells, that is, Stat3 is indeed required for this process. We will now investigate the pathway of differentiation, as opposed to cell multiplication, by examining the effect of a hyperactive form of Stat3, which is able to cause overproliferation of the cells. We will also study the role of other molecules that we found to interact with Stat3 (called Rac, Cdc42, IL6 and gp130), by increasing or decreasing their activity in the cell using drugs or genetic methods, then examining the effect that these manipulations have upon differentiation. Anticipated benefits and significance: The project proposed may expose a novel pathway leading from cadherin engagement to Stat3 activation, as being a central determinant of the balance between cell differentiation vs multiplication, that is may be a key for the decision of the cell to follow one or the other of these fundamentally opposite paths. These results will reveal the molecular underpinnings of fundamental biological processes. The knowledge gained may be applicable to other types of situations where cadherin engagement and growth arrest are necessary, such as differentiation of fat cells, muscle or cartilage with a large variety of applications, such as lactation, obesity, immunity, cancer or embryonic development. The students who advance this research will obtain valuable expertise on Cell Biology mechanisms and make an impact in both industrial and Academic research.