![]() ![]() Metabolic orchestration of cell death by AMPK-mediated phosphorylation of RIPK1. Zhang T, Xu D, Trefts E, Lv M, Inuzuka H, Song G, Liu M, Lu J, Liu J, Chu C, Wang M, Wang H, Meng H, Liu H, Zhuang Y, Xie X, Dang F, Guan D, Men Y, Jiang S, Jiang C, Dai X, Liu J, Wang Z, Yan P, Wang J, Tu Z, Babuta M, Erickson E, Hillis AL, Dibble CC, Asara JM, Szabo G, Sicinski P, Miao J, Lee YR, Pan L, Shaw RJ, Yuan J, Wei W. Moreover, we are generating novel mutant mouse strains that will help explain the role of cell-cycle machinery at the organismal, cellular, and molecular levels. We are currently using these knockout strains, and cells derived from them, as tools to study the role of particular cyclin proteins in normal cell proliferation and in oncogenesis of breast cancers, in particular. Hence, the normal, physiologic role for cyclin D1 is to drive hormone-induced mammary epithelial proliferation, while overexpression of the very same cyclin plays a causative role in human breast cancers. For example, we discovered that cyclin D1-deficient mice develop hormone-insensitive mammary glands. ![]() We found that each of these proteins is required for proliferation in a very narrow, highly specific sets of tissues. To understand the role played by these various cyclin proteins in normal development and in cancer, we generated several genetically engineered 'knockout' mouse strains lacking different cyclin proteins. Importantly, because agents that antagonize this cyclin have been shown to shut off the proliferation of breast cancer cells grown in vitro, overexpression of cyclin D1 seems to play a causative role in mammary tumorigenesis. For example, more than 50% of human breast cancers contain highly elevated levels of a particular cyclin protein, termed cyclin D1. Abnormal expression of cyclins is seen in a great number of human cancers. ![]() The key components of this machinery are proteins termed cyclins. The cell-cycle machinery is present in every single cell, and it can be thought of as the molecular engine that drives cell proliferation. After they are received by the cells, these growth-promoting or growth-inhibitory signals are transmitted to the so-called cell-cycle machinery operating in the nucleus. The proliferation of mammalian cells is tightly controlled by numerous external signals.
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