Inhibitor of growth tumor suppressors in cancer progression

The inhibitor of growth (ING) family of tumor suppressors has five members and is implicated in the control of apoptosis, senescence, DNA repair, and cancer progression. However, little is known about ING activity in the regulation of cancer progression. ING members and splice variants seem to behave differently with respect to cancer invasion and metastasis. Interaction with histone trimethylated at lysine 4 (H3K4me3), hypoxia inducible factor-1 (HIF-1), p53, and nuclear factor kappa-B (NF-κB) are potential mechanisms by which ING members exert effects on invasion and metastasis. Subcellular mislocalization, rapid protein degradation, and to a lesser extent ING gene mutation are among the mechanisms responsible for inappropriate ING levels in cancer cells. The aim of this review is to summarize the different roles of ING family tumor suppressors in cancer progression and the molecular mechanisms involved.     

The Akt-associated microRNAs

As master gene regulators, microRNAs are involved in diverse cellular pathways. It is well known that microRNAs are often dysregulated in many types of cancer and other human diseases. In cancer, microRNAs may function as oncogenes or tumor suppressors. Interestingly, recent evidence suggests that microRNA-mediated gene regulation interconnects with the Akt pathway, forming an Akt–microRNA regulatory network. MicroRNAs and Akt in this network work together to exert their cellular functions. Thus, a better understanding of this Akt–microRNA regulatory network is critical to successful targeting of the PI3K/Akt pathway for cancer therapy. We review recent advances in the understanding of how microRNAs affect Akt activity as well as how microRNAs are regulated through the Akt pathway. We also briefly discuss the clinical implication of gene regulation mediated through Akt-associated microRNAs.     

MicroRNAs in breast cancer initiation and progression

The emerging role of microRNAs (miRNAs) in the epigenetic regulation of many cellular processes has become recognized in both basic research and translational medicine as an important way that gene expression can be fine-tuned. Breast cancer is the most frequent cancer in women, with about one million new cases diagnosed each year worldwide. Starting with the early work of miRNA profiling, more effort has now been put on functions of miRNAs in normal mammary stem cells, breast cancer initiating cells and metastatic cells, and therapy-resistant cancer cells. Future translational studies may focus on identifying miRNA signatures as cancer biomarkers and developing miRNA-based targeted therapeutics.     

Directed evolution of enzymes for biocatalysis and the life sciences

Engineering the specificity and properties of enzymes and proteins within rapid time frames has become feasible with the advent of directed evolution. In the absence of detailed structural and mechanistic information, new functions can be engineered by introducing and recombining mutations, followed by subsequent testing of each variant for the desired new function. A range of methods are available for mutagenesis, and these can be used to introduce mutations at single sites, targeted regions within a gene or randomly throughout the entire gene. In addition, a number of different methods are available to allow recombination of point mutations or blocks of sequence space with little or no homology. Currently, enzyme engineers are still learning which combinations of selection methods and techniques for mutagenesis and DNA recombination are most efficient. Moreover, deciding where to introduce mutations or where to allow recombination is actively being investigated by combining experimental and computational methods. These techniques are already being successfully used for the creation of novel proteins for biocatalysis and the life sciences.Received 8 June 2004; received after revision 22 July 2004; accepted 2 August 2004