The Quaking family of RNA-binding proteins: coordinators of the cell cycle and differentiation.

Transcriptional and epigenetic control of gene expression is critical for cell fate specification, commitment and terminal differentiation during development. However, also regulatory RNAs and RNA-binding proteins have emerged as critical developmental regulators. They control various aspects of mRNA metabolism such as stability, translation, and localization, and similar to some transcriptional regulators, such as PAX5 and MYC, they can affect gene expression on a massive scale. Consistently, defects in many mRNA regulators have been implicated in a number of human disorders, including cancer. Quaking-related (QR) proteins are conserved RNA-binding proteins of the STAR (signal transduction and activation of RNA) family. QR proteins regulate expression of diverse mRNA targets by various mechanisms, play essential roles in a whole host of developmental decisions, and function as tumor suppressors. This review discusses several best-studied members of the QR family, their developmental functions, molecular mechanisms, representative mRNA targets, and their intriguing ability to coordinately control the cell cycle and a wide range of differentiation pathways.

Translational repression of cyclin E prevents precocious mitosis and embryonic gene activation during C. elegans meiosis.

Germ cells, the cells that give rise to sperm and egg, maintain the potential to recreate all cell types in a new individual. This wide developmental potential, or totipotency, is manifested in unusual tumors called teratomas, in which germ cells undergo somatic differentiation. Although recent studies have implicated RNA regulation, the mechanism that normally prevents the loss of germ cell identity remains unexplained. In C. elegans, a teratoma is induced in the absence of the conserved RNA-binding protein GLD-1. Here, we demonstrate that GLD-1 represses translation of CYE-1/cyclin E during meiotic prophase, which prevents germ cells from re-entering mitosis and inducing embryonic-like transcription. We describe a mechanism that prevents precocious mitosis in germ cells undergoing meiosis, propose that this mechanism maintains germ cell identity by delaying the onset of embryonic gene activation until after fertilization, and provide a paradigm for the possible origin of human teratomas.

Analysis of the CD33-related siglec family reveals that Siglec-9 is an endocytic receptor expressed on subsets of acute myeloid leukemia cells and absent from normal hematopoietic progenitors.

CD33 (Siglec-3) is expressed on most acute myeloid leukemia (AML) cells and is currently being exploited as a therapeutic target. The purpose of this study was to investigate the expression pattern and potential utility of the seven recently described CD33-related siglecs as markers in AML. Besides CD33, Siglec-9 was the most highly expressed, particularly on AML cells with features of monocytic differentiation that also expressed Siglecs-5 and -7. Siglec-9 was absent from normal bone marrow myeloid progenitors but present on monocytic precursors. Using primary AML cells or transfected rat basophilic leukemia cells, Siglec-9 mediated rapid endocytosis of anti-Siglec-9 mAb. In contrast to CD33 and Siglec-5, levels of soluble Siglec-9 were low or undetectable in bone marrow plasma from AML patients and serum from normal donors. These features suggest that Siglec-9 provides not only a useful marker for certain subsets of AML, but also a potential therapeutic target.