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Metastasis is a multistep process that involves the dissemination of cells from the primary tumor and colonization of distant secondary organs. Epithelial cells at the invasive front of a carcinoma acquire an enhanced migratory phenotype in a process called epithelial-to-mesenchymal transition (EMT). This cellular plasticity seems to drive the initiation of metastasis. Identifying important molecules and understanding their molecular mechanisms is a key to cancer prognosis and the development of therapeutics for late stage malignancies. Recent advances in sequencing technology uncovered that the mammalian genome is pervasively transcribed into many nonprotein-coding RNAs including the class of long noncoding RNA, a.k.a. lncRNA. Several lncRNAs are differentially expressed in carcinomas and they are emerging as potent regulators of tumor progression and metastasis. Here, we review the diverse molecular mechanisms, cellular roles and regulatory patterns that are becoming apparent for the noncoding transcriptome. Chromatin modification, epigenetic regulation, alternative splicing and translational control by MALAT1, HOTAIR and TRE lncRNAs represent important examples of lncRNA-mediated control of cell migration and invasion, EMT and metastasis. Beyond these better characterized examples, numerous additional transcripts have been associated with cancer metastasis, but their functional roles await their discovery.

Cyclin A1 plays a critical role in hematopoietic malignancies, notably, acute myeloid leukemia. The molecular mechanisms of cyclin A1 action are incompletely understood. Here, we show that cyclin A1 functions are mediated by the retinoblastoma and the Ku70 pathway. High levels of cyclin A1 and the associated CDK2 kinase activity were associated with increasing levels of phosphorylated retinoblastoma in vivo. UV irradiation induced a switch of the CDK2 towards cyclin A1, with accordance to changes in CDK2 kinase activity. The C-terminus of cyclin A1 directly interacted with Ku70, and DNA binding activity of Ku70 was modulated by cyclin A1/CDK2 and phosphatase treatment. Cyclin A1-deficiency induced by shRNA increased apoptosis that is induced by DNA damage and death receptor ligands. Taken together, these analyses demonstrate that cyclin A1 exerts antiapoptotic functions by interacting with retinoblastoma and Ku proteins in leukemia cells.

Mitotic and meiotic cell cycle regulation is essential for normal development and tumor prevention. The underlying molecular mechanisms are not completely characterized. The aim of our analysis was to derive a global expression map of cell cycle regulators in mitosis and meiosis. First, the expression of cyclins, CDKs and CDK inhibitors was determined during postnatal testis maturation in mice using microarrays and quantitative RT-PCR. The abundance of cyclins A1, B2, K, M4, CDK2, all CDKLs, CDKN2c, CDKN2d and INCA1 increased during testis maturation. In contrast, cyclins A2, B1, D2, G1, G2, CDK1, CDK4 and CDK2AP1 showed a maturation-associated decrease. Gene expression profiles of isolated germ cells and testicular somatic cells confirmed these results. Second, we determined cyclin expression patterns in human normal and malignant testis samples (n = 36) modeling the reciprocal difference between meiosis and mitosis. Testicular tumors strictly expressed cell cycle regulators identified in mitotically dividing germ cells. Expression of several transcripts was histology-specific in testicular tumors, providing novel molecular markers and potential therapeutic targets. Taken together, our data provide a comprehensive expression map of cell cycle regulators at the switch between mitosis and meiosis in testis development and in cancerogenesis. © 2005 Wiley-Liss, Inc.

TIP47 (tail-interacting protein of 47 kDa) binds to the cytoplasmic domains of mannose 6-phosphate receptors and is required for their transport from endosomes to the trans-Golgi network in vitro and in living cells. TIP47 occurs in cytosol as an oligomer; it chromatographs with an apparent mass of ∼ 300 kDa and displays an S-value of ∼ 13. Recombinant TIP47 forms homo-oligomers that are likely to represent hexamers, as determined by chemical cross-linking. Removal of TIP47 residues 1–151 yields a protein that behaves as a monomer upon gel filtration, yet is fully capable of binding mannose 6-phosphate receptor cytoplasmic domains. The presence of an oligomerization domain in the N-terminus of TIP47 was confirmed by expression of N-terminal residues 1–133 or 1–257 in mammalian cells. Co-expression of full-length TIP47 with either of these fragments led to the formation of higher-order aggregates of wild-type TIP47. Furthermore, the N-terminal domains expressed alone also occurred as oligomers. These studies reveal an N-terminal oligomerization domain in TIP47, and show that oligomerization is not required for TIP47 recognition of mannose 6-phosphate receptors. However, oligomerization is required for TIP47 stimulation of mannose 6-phosphate receptor transport from endosomes to the trans-Golgi in vivo.