Aspects of cell growth control illustrated by the Schwann cell.

The control of cell biogenesis remains poorly understood, despite being critical for the development and maintenance of all organisms. Studies in vitro and in vivo using the Schwann cell, the glial cell of the peripheral nervous system, have provided important insights into cell growth control. These studies have demonstrated how instructive growth factor signals can control cell growth rates, cell size and organelle biogenesis and how deregulated cell growth can contribute to diseases, such as cancer. Additional studies on Schwann cells highlight the importance of cell size control within a tissue--the size of myelinating Schwann cells is coupled to the size of the axon they ensheath, which is necessary for efficient nerve conduction.

Loss of Rb cooperates with Ras to drive oncogenic growth in mammalian cells.

BACKGROUND: The p53, Rb, and Ras/PI3K pathways are implicated in the development of the majority of human cancers. A number of studies have established that these pathways cooperate at the level of the cell cycle leading to loss of normal proliferative controls. Here we have investigated how these signals influence a second critical component of tumor formation-cell growth. RESULTS: We find that oncogenic Ras is sufficient to drive growth via the canonical growth pathway, PI3K-AKT-TOR; however, it does so relatively weakly and p53 loss does not drive cell growth at all. Importantly, we identify a novel role for the Rb family of tumor suppressors in directing cell growth via a signaling pathway distinct from PI3K-AKT-TOR and via an E2F-independent mechanism. However, we find that strong, sustained growth requires Rb loss together with Ras signaling, identifying an additional mechanism by which these oncogenic pathways cooperate and a critical role for Ras in preserving the uptake of extracellular nutrients required for biogenesis. CONCLUSIONS: We have identified a new role for the Rb family in cell biogenesis and show that, as for other processes associated with tumor development, oncogenic cell growth is dependent on cooperating oncogenes.

KSHV-encoded miRNAs target MAF to induce endothelial cell reprogramming.

Kaposi sarcoma herpesvirus (KSHV) induces transcriptional reprogramming of endothelial cells. In particular, KSHV-infected lymphatic endothelial cells (LECs) show an up-regulation of genes associated with blood vessel endothelial cells (BECs). Consequently, KSHV-infected tumor cells in Kaposi sarcoma are poorly differentiated endothelial cells, expressing markers of both LECs and BECs. MicroRNAs (miRNAs) are short noncoding RNA molecules that act post-transcriptionally to negatively regulate gene expression. Here we validate expression of the KSHV-encoded miRNAs in Kaposi sarcoma lesions and demonstrate that these miRNAs contribute to viral-induced reprogramming by silencing the cellular transcription factor MAF (musculoaponeurotic fibrosarcoma oncogene homolog). MAF is expressed in LECs but not in BECs. We identify a novel role for MAF as a transcriptional repressor, preventing expression of BEC-specific genes, thereby maintaining the differentiation status of LECs. These findings demonstrate that viral miRNAs could influence the differentiation status of infected cells, and thereby contribute to KSHV-induced oncogenesis.