The ubiquitin-proteasome system plays a pivotal role in the sequence of events leading to cell division known as the cell cycle. Not only does ubiquitin-mediated proteolysis constitute a critical component of the core oscillator that drives the cell cycle in all eukaryotes, it is also central to the mechanisms that ensure that the integrity of the genome is maintained. These functions are primarily carried out by two families of E3 ubiquitin ligases, the Skp/cullin/F-box-containing and anaphase-promoting complex/cyclosome complexes. However, beyond those functions associated with regulation of central cell cycle events, many peripheral cell cycle-related processes rely on ubiquitylation for signaling, homeostasis, and dynamicity, involving additional types of ubiquitin ligases and regulators. We are only beginning to understand the diversity and complexity of this regulation.

Hyperglycemia is a common feature of diabetes mellitus, considered as a risk factor for cancer. However, its direct effects in cancer cell behavior are relatively unexplored. Herein we show that high glucose concentration induces aberrant glycosylation, increased cell proliferation, invasion and tumor progression of colon cancer. By modulating the activity of the rate-limiting enzyme, glutamine-fructose-6-phosphate amidotransferase (GFAT), we demonstrate that hexosamine biosynthetic pathway (HBP) is involved in those processes. Biopsies from patients with colon carcinoma show increased levels of GFAT and consequently aberrant glycans’ expression suggesting an increase of HBP flow in human colon cancer. All together, our results open the possibility that HBP links hyperglycemia, aberrant glycosylation and tumor malignancy, and suggest this pathway as a potential therapeutic target for colorectal cancer.

Upon antigen stimulation, lymphocytes enter in cell cycle and proliferate, and most of the activated T cells die by apoptosis. Many of the proteins that regulate lymphocyte activation are Under the control of transcription factors belonging to the NFAT family. As previously demonstrated, NFATC2-/- mice consistently showed a marked increase in lymphocyte proliferation. Here, we evaluate the role of NFATC2 in regulating lymphocyte proliferation and its involvement in the control of cell cycle progression during lymphocyte activation. NFATC2-/- lymphocytes, including CD4+ T cells and B cells, hyperproliferated upon stimulation when compared with NFATC2+/+ cells. Analysis of cell death demonstrated that NFATC2-/- lymphocytes displayed an increased rate of apoptosis after antigen stimulation in addition to the hyperproliferation. Cell cycle analysis after antigen stimulation showed that NFATC2-/- cultures contained more cycling cells when compared with NFATC2+/+ cultures, which is related to a shortening in time of cell division upon activation. Furthermore, hyperproliferation of NFATC2-/- lymphocytes is correlated to an overexpression of cyclins A2, B1, E, and F. Taken together, our results suggest that the NFATC2 transcription factor plays an important role in the control of cell cycle during lymphocyte activation and may act as an inhibitor of cell proliferation in normal cells.

Allergic diseases have been closely related to Th2 immune responses, which are characterized by high levels of interleukin (IL)

The nuclear factor of activated T cells (NFAT) family of transcription factors has been primarily identified in immune cells; however, these proteins have been recently found to be functionally active in several other non-immune cell types. NFAT proteins are activated upon different stimuli that lead to increased intracellular calcium levels. Regardless of their widely known cytokine gene expression properties, NFATs have been shown to regulate other genes related to cell cycle progression, cell differentiation and apoptosis, revealing a broader role for these proteins in normal cell physiology. Several reports have addressed the participation of NFATs in many aspects of malignant cell transformation and tumorigenic processes. In this review, we will discuss the involvement of the different NFAT family members in the regulation of cell cycling, differentiation and tumor formation, and also its implications on oncogenesis. Better understanding the mechanisms by which NFATs regulate cell cycle and tumor-related events should be relevant for the development of rational anti-cancer therapies.