Charting the complex composite nature of centrosomes, primary cilia and centriolar satellites.

The centrosome and its associated structures of the primary cilium and centriolar satellites have been established as central players in a plethora of cellular processes ranging from cell division to cellular signaling. Consequently, defects in the structure or function of these organelles are linked to a diverse range of human diseases, including cancer, microcephaly, ciliopathies, and neurodegeneration. To understand the molecular mechanisms underpinning these diseases, the biology of centrosomes, cilia, and centriolar satellites has to be elucidated. Central to solving this conundrum is the identification, localization, and functional analysis of all the proteins that reside and interact with these organelles. In this review, we discuss the technological breakthroughs that are dissecting the molecular players of these enigmatic organelles with unprecedented spatial and temporal resolution.

MicroRNA-874-mediated inhibition of the major G1/S phase cyclin, CCNE1, is lost in osteosarcomas.

The tumor microenvironment is characterized by nutrient-deprived conditions in which the cancer cells have to adapt for survival. Serum starvation resembles the growth factor deprivation characteristic of the poorly vascularized tumor microenvironment and has aided in the discovery of key growth regulatory genes and microRNAs (miRNAs) that have a role in the oncogenic transformation. We report here that miR-874 down-regulates the major G1/S phase cyclin, cyclin E1 (CCNE1), during serum starvation. Because the adaptation of cancer cells to the tumor microenvironment is vital for subsequent oncogenesis, we tested for miR-874 and CCNE1 interdependence in osteosarcoma cells. We observed that miR-874 inhibits CCNE1 expression in primary osteoblasts, but in aggressive osteosarcomas, miR-874 is down-regulated, leading to elevated CCNE1 expression and appearance of cancer-associated phenotypes. We established that loss of miR-874-mediated control of cyclin E1 is a general feature of osteosarcomas. The down-regulation of CCNE1 by miR-874 is independent of E2F transcription factors. Restoration of miR-874 expression impeded S phase progression, suppressing aggressive growth phenotypes, such as cell invasion, migration, and xenograft tumors, in nude mice. In summary, we report that miR-874 inhibits CCNE1 expression during growth factor deprivation and that miR-874 down-regulation in osteosarcomas leads to CCNE1 up-regulation and more aggressive growth phenotypes.