MicroRNAs: Genomics, Biogenesis, Mechanism, and Function

The hallmarks of cancer.

Recent data have expanded the concept that inflammation is a critical component of tumour progression. Many cancers arise from sites of infection, chronic irritation and inflammation. It is now becoming clear that the tumour microenvironment, which is largely orchestrated by inflammatory cells, is an indispensable participant in the neoplastic process, fostering proliferation, survival and migration. In addition, tumour cells have co-opted some of the signalling molecules of the innate immune system, such as selectins, chemokines and their receptors for invasion, migration and metastasis. These insights are fostering new anti-inflammatory therapeutic approaches to cancer development.

Inflammation and cancer

In contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, most cancer cells instead rely on aerobic glycolysis, a phenomenon termed “the Warburg effect.” Aerobic glycolysis is an inefficient way to generate adenosine 5′-triphosphate (ATP), however, and the advantage it confers to cancer cells has been unclear. Here we propose that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass (e.g., nucleotides, amino acids, and lipids) needed to produce a new cell. Supporting this idea are recent studies showing that (i) several signaling pathways implicated in cell proliferation also regulate metabolic pathways that incorporate nutrients into biomass; and that (ii) certain cancer-associated mutations enable cancer cells to acquire and metabolize nutrients in a manner conducive to proliferation rather than efficient ATP production. A better understanding of the mechanistic links between cellular metabolism and growth control may ultimately lead to better treatments for human cancer.

/pdf/understanding-the-warburg-effect-the-metabolic-requirements-t1cwrmjv80.pdf

Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation

Microarrays can measure the expression of thousands of genes to identify changes in expression between different biological states. Methods are needed to determine the significance of these changes while accounting for the enormous number of genes. We describe a method, Significance Analysis of Microarrays (SAM), that assigns a score to each gene on the basis of change in gene expression relative to the standard deviation of repeated measurements. For genes with scores greater than an adjustable threshold, SAM uses permutations of the repeated measurements to estimate the percentage of genes identified by chance, the false discovery rate (FDR). When the transcriptional response of human cells to ionizing radiation was measured by microarrays, SAM identified 34 genes that changed at least 1.5-fold with an estimated FDR of 12%, compared with FDRs of 60 and 84% by using conventional methods of analysis. Of the 34 genes, 19 were involved in cell cycle regulation and 3 in apoptosis. Surprisingly, four nucleotide excision repair genes were induced, suggesting that this repair pathway for UV-damaged DNA might play a previously unrecognized role in repairing DNA damaged by ionizing radiation.

/pdf/significance-analysis-of-microarrays-applied-to-the-ionizing-10j4beasgw.pdf

Significance analysis of microarrays applied to the ionizing radiation response

The cell cycle of Schizosaccharomyces pombe in continuous culture is controlled at two steps, one which limits the transition from G1 to S phase and the other which determines the timing of cell division. We have investigated, by means of flow-cytofluorometry, the cell cycle characteristics of nutritionally starved cells in stationary phase. Cells were shown to become arrested in either G1 or G2, in ratios which depended on the composition of the growth medium. G1 and G2 stationary phase cells share certain properties. (1) They become relatively resistant to heat shock. (2) They can reenter the cell cycle after subculture into fresh medium. (3) The G1 and G2 arrested populations have equal long-term viability in stationary phase. (4) Both populations require the activity of the cdc2+ gene for reentry into the cell cycle. We suggest that cell cycle arrest in stationary phase is regulated by the activity of the same G1 and G2 controls which limit the rate of cell cycle progression in continuous culture. The data demonstrate that in fission yeast the transition from G1 to S phase does not mark a point of commitment to the completion of the cell cycle.

Fission yeast enters the stationary phase G0 state from either mitotic G1 or G2

https://www.cell.com/cell/pdf/0092-8674(89)90339-5.pdf

Involvement of a type 1 protein phosphatase encoded by bws1+ in fission yeast mitotic control

Chromobox 7 (CBX7) is a chromobox family protein and a component of the Polycomb repressive complex 1 (PRC1) that extends the lifespan of cultured epithelial cells and can act independently of BMI-1 to repress the INK4a/ARF tumor suppressor locus. To determine whether CBX7 might be oncogenic, we examined its expression pattern in a range of normal human tissues and tumor samples. CBX7 was expressed at high levels in germinal center lymphocytes and germinal center-derived follicular lymphomas, where elevated expression correlated with high c-Myc expression and a more advanced tumor grade. By targeting Cbx7 expression to the lymphoid compartment in mice, we showed that Cbx7 can initiate T cell lymphomagenesis and cooperate with c-Myc to produce highly aggressive B cell lymphomas. Furthermore, Cbx7 repressed transcription from the Ink4a/Arf locus and acted epistatically to the Arf-p53 pathway during tumorigenesis. These data identify CBX7 as a chromobox protein causally linked to cancer development and may help explain the low frequency of INK4a/ARF mutations observed in human follicular lymphoma.

https://www.pnas.org/content/pnas/104/13/5389.full.pdf

David Beach

Papers

Fission yeast enters the stationary phase G0 state from either mitotic G1 or G2

Involvement of a type 1 protein phosphatase encoded by bws1+ in fission yeast mitotic control

Role of the chromobox protein CBX7 in lymphomagenesis

Physical Interaction of Mammalian CDC37 with CDK4

Subcellular distribution of p21 and PCNA in normal and repair-deficient cells following DNA damage