生物谷报道：Brown医学院和Rhode Island医院的研究者们最近发现了某些关键蛋白质的激活同患癌有关，特别是目前美国常见的乳腺癌及前列腺癌。由生物化学专家组成的研究小组发现了一种新的化学修饰过程－STAT3的激活。STAT3在胚胎生长发育中被称作信号蛋白，促进细胞生长、分裂和迁徙。而在成人，它被认为是静止的，一旦被持续活化，将导致乳腺细胞和前列腺细胞分裂、转移到全身。科学家们现在怀疑某种环境因素，诸如饮食中摄入高动物脂肪和高激素，可能激活STAT3。
过去十年里，有关细胞内的STAT3的激活途径争论激烈。一种已知的激活环节是STAT3蛋白中酪氨酸和丝氨酸残基的磷酸化。本次研究发现了第二个激活环节：乙酰化－另一种氨基酸残基，如赖氨酸残基的化学修饰模式。这也许可以解释为何单纯阻断STAT3磷酸化的药物并不能完全阻断肿瘤生长和侵袭全身的原因。了解了这两种STAT3活化的化学过程将有助于开发更好的抗癌药物。
使用分光比色计，经过两年对正常STAT3蛋白和变异STAT3蛋白的研究，对人工培养细胞株中STAT3蛋白的47个赖氨酸残基逐个乙酰化，观察是否能激活STAT3，研究人员最终发现了元凶：685位的赖氨酸残基。
据美国癌症学会报道，2004年共诊断了217,440例乳腺癌患者和230,110例前列腺癌患者。现在，能同时阻断酪氨酸磷酸化和丝氨酸乙酰化的药物将成为治疗这两种癌症的研究目标（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
