Article Title: c-Myc-regulated microRNAs modulate E2F1 expression
Authors: O'Donnell, KA;Wentzel, EA;Zeller, KI;Dang, CV;Mendell, JT
Journal: NATURE
Volume: 435
Issue: 7043
Page: 839-843
Q：Why do you think your paper is highly cited?
A：It has recently become clear that abnormal microRNA expression is a very frequent, if not ubiquitous, characteristic of cancer cells. Nevertheless, the mechanisms that govern microRNA expression in normal and pathologic states are poorly understood. Our paper was the first to show that an oncogenic transcription factor directly regulates microRNA expression, providing molecular insight into one mechanism through which microRNAs become dysregulated in cancer.
Moreover, the specific microRNAs that we studied in this paper have subsequently been shown by multiple laboratories to be frequently overexpressed in cancer cells and to possess oncogenic activity. Thus, our findings have proven to be broadly relevant to our understanding of microRNA regulation and function in disease states.
Q：Does it describe a new discovery or a new methodology that's useful to others?
A：The discovery that an oncogene regulates microRNA expression provides an entirely new mechanism through which an oncogene can promote tumorigenesis. More generally, c-Myc, the oncogene that we focused on, has been studied for over 20 years, but microRNA regulation represents an entirely new aspect of its function. This emphasizes the potential for many well-studied gene products to have completely unanticipated functions involving microRNAs.
Q：Could you summarize the significance of your paper in layman's terms?
A：Mechanisms that control when genes are turned on and turned off are critical for maintaining normal cellular behavior. For example, inappropriate activation of a gene that promotes the growth of cells can lead to the development of a tumor. A similar outcome may result from inappropriate repression of a gene that normally suppresses cellular proliferation.
Less than five years ago, an entirely new mechanism of regulating the level of activity of a gene was discovered. This new regulatory pathway relies on tiny molecules called microRNAs which, when produced by a cell, are able to turn off specific sets of genes. It was subsequently shown that many different types of cancer cells produce abnormal amounts of microRNAs.
We discovered that a protein that is known to potently drive cellular proliferation and tumorigenesis activates expression of a specific group of microRNAs. These findings provide insight into the mechanisms that regulate microRNA expression in normal cells and cancer cells.
Q：How did you become involved in this research, and were any problems encountered along the way?
A：Some of the earliest microRNAs that were discovered in model organisms were found to regulate processes such as cellular differentiation, proliferation, and death. Since abnormalities in these processes are also fundamental to the development of cancer, we speculated that microRNAs might be dysregulated in this disease.
To test this hypothesis, we developed methodologies to gloabally monitor microRNA expression profiles. As we began using these systems, we realized that microRNAs might also be directly regulated by oncogenes during neoplastic transformation. This led us to begin experimenting with c-Myc.
Joshua Mendell, M.D., Ph.D.
Assistant Professor
Institute of Genetic Medicine
Johns Hopkins University School of Medicine
Baltimore, MD, USA
领域：分子生物学和遗传学
文章题名：c-Myc-控制的微小RNAs调节E2F1表达
作者：O'Donnell, KA;Wentzel, EA;Zeller, KI;Dang, CV;Mendell, JT
杂志：NATURE
卷：435
期：7043
页：839-843
问：为什么你认为你的论文被引用得多？
答： 近年来已经明确异常的微小RNAs在肿瘤细胞中经常（即使不是持续的）、有特征性地表达。然而，对于控制微小RNAs表达的正常及病理机制却知之甚少。我们的论文第一次揭示了一种癌基因转录因子直接调控微小RNAs表达，通过肿瘤细胞中微小RNAs失调这一机制提供了分子水平上的见解。
而且，论文中所研究的特异微小RNAs随后被多家实验室证明在肿瘤细胞中呈高表达且拥有致癌活性。因此，已显示出我们的研究同疾病状态下微小RNAs的调节及其功能广泛相关。
问：论文记述了对其它领域有用的新发现或新的方法学吗？
答：癌基因调控微小RNAs的表达这一发现为癌基因能够促进肿瘤的发生提供了全新的机制。 而且，我们所关注的c-Myc癌基因已被研究了20年以上，但是微小RNAs的调控却代表了其功能上的全新的一面。这就为许多研究得较为深入的基因产品着重提了其有关微小RNAs的完全不可预测的功能。
问：你能用非专业术语总结一下论文的意义吗？
答：控制基因何时启动、何时关闭的机制对于维持正常的细胞行为至关重要。例如，促进细胞生长的基因异常激活能导致肿瘤的形成。同样，抑制细胞增殖的基因异常失活也能导致肿瘤的形成。
不到5年前，发现了基因调控水平上的活性这一全新的机制。这个新的调节途径依赖于被称为微小RNAs的微小分子，当由细胞产生时，它能够关闭特异的基因程序。
我们发现一种具有启动细胞增殖和肿瘤形成潜能的蛋白质可激活特异的微小RNAs群体。这些发现为正常细胞及肿瘤细胞微小RNAs的表达调控提供了见解。
问：你是怎样开始从事这项研究的，研究过程中遇到问题了吗？
答：一些在生物体模型中发现的早期微小RNAs被发现能够调节诸如细胞分化、增殖及死亡一类的程序。既然这些程序的异常对于肿瘤的发展也是重要的，因此我们猜测肿瘤患者的微小RNAs可能是失调的。
为了验证这一假说，我们发展了监测微小RNAs表达谱的方法学。当开始运用这些方法时，我们认识到肿瘤转化过程中癌基因也可直接调节微小RNAs。这就使得实验从c-Myc开始。
编辑：西门吹血
