生物谷報道：Brown醫(yī)學院和Rhode Island醫(yī)院的研究者們最近發(fā)現(xiàn)了某些關鍵蛋白質(zhì)的激活同患癌有關，特別是目前美國常見的乳腺癌及前列腺癌,。由生物化學專家組成的研究小組發(fā)現(xiàn)了一種新的化學修飾過程－STAT3的激活,。STAT3在胚胎生長發(fā)育中被稱作信號蛋白，促進細胞生長,、分裂和遷徙,。而在成人，它被認為是靜止的,，一旦被持續(xù)活化,，將導致乳腺細胞和前列腺細胞分裂、轉移到全身,?？茖W家們現(xiàn)在懷疑某種環(huán)境因素，諸如飲食中攝入高動物脂肪和高激素,，可能激活STAT3,。
過去十年里，有關細胞內(nèi)的STAT3的激活途徑爭論激烈,。一種已知的激活環(huán)節(jié)是STAT3蛋白中酪氨酸和絲氨酸殘基的磷酸化,。本次研究發(fā)現(xiàn)了第二個激活環(huán)節(jié)：乙酰化－另一種氨基酸殘基,，如賴氨酸殘基的化學修飾模式,。這也許可以解釋為何單純阻斷STAT3磷酸化的藥物并不能完全阻斷腫瘤生長和侵襲全身的原因。了解了這兩種STAT3活化的化學過程將有助于開發(fā)更好的抗癌藥物,。
使用分光比色計,，經(jīng)過兩年對正常STAT3蛋白和變異STAT3蛋白的研究，對人工培養(yǎng)細胞株中STAT3蛋白的47個賴氨酸殘基逐個乙?；?，觀察是否能激活STAT3，研究人員最終發(fā)現(xiàn)了元兇：685位的賴氨酸殘基,。
據(jù)美國癌癥學會報道,，2004年共診斷了217,440例乳腺癌患者和230,110例前列腺癌患者。現(xiàn)在,，能同時阻斷酪氨酸磷酸化和絲氨酸乙?；乃幬飳⒊蔀橹委熯@兩種癌癥的研究目標（http://www.bioon.com/）,。
Surprising Study Reveals How Cancer-Causing Protein Activates
Researchers at Brown Medical School and Rhode Island Hospital have shed new light on the activation of a protein key to the development of cancers, particularly breast and prostate cancer, the most commonly diagnosed cancers in the United States.
The team of cell biologists has discovered a new chemical modification that activates STAT3. This so-called signaling protein is important for embryonic growth and development, helping cells grow, duplicate and migrate. In adulthood, STAT3 presumably falls dormant, but its unexpected and continuous activation causes breast and prostate cells to develop and move through the body.
Eugene Chin, M.D., a Rhode Island Hospital researcher and assistant professor (research) of surgery at Brown Medical School, said experts suspect that environmental factors, such as a diet rich in animal fat and hormones, may activate STAT3.
How the protein is turned on inside cells has been the subject of fiercely competitive research during the last decade. One known trigger is phosphorylation, which modifies some of the tyro-sine and serine amino acids that make up the STAT3 protein. Chin and his team found a second trigger: acetylation, another chemical process that modifies amino acids, such as lysine. Chin said this finding might explain why drugs that only block STAT3 phosphorylation cannot completely stop cancer cells from growing and invading other parts of the body.
"Both tyrosine phosphorylation and lysine acetylation modifications are important events for STAT3 to stimulate cancer cell growth and metastasis," Chin said. "That's why the finding is so exciting. Now that we know more about STAT3 activation, we can create better drugs."
Their findings are published in the current issue of Science.
Paul Yuan, a post-doctoral fellow in Chin's Rhode Island Hospital lab and the lead author of the paper, painstakingly mutated 47 lysine amino acids and tested each one in cultured cells to see if it activated STAT3. Using this method, Yuan was able to isolate the culprit: Lys685, one of as many as 780 amino acids that are strung together to make the protein.
Yuan corroborated the finding by testing both a normal and mutated version of STAT3 in a mass spectrometer. The machine smashes the protein into amino acids then sequences these building blocks. The work took nearly two years to complete.
Chin said the research provides an important target for drugs in treating breast and prostate cancers that are common in the United States. According to the American Cancer Society, an estimated 217,440 Americans were diagnosed with breast cancer and 230,110 were diagnosed with prostate cancer in 2004.
"Finding a drug to block both tyrosine phosphorylation and lysine acetylation of STAT3 protein should be a more effective cancer treatment," Chin said.
The research team also included Ying-jie Guan, a post-doctoral fellow in the lab, and Devasis Chatterjee, an assistant professor (research) of Medicine at Brown Medical School.
Source: Brown University
