Stem cells are characterized by well classified energetic and biosynthetic demands compared to quiescent differentiated cells.96 Changing gears between the glycolytic and mitochondrial oxphos pathways triggers differentiation or reprogramming to pluripotency that are furthermore accompanied by consequent changes in cell cycle, biomass, metabolite levels, and redox state. virus integration site 1) was discovered as a frequent target of the Moloney virus insertion, resulting in virally accelerated B-lymphoid tumors, hence its name.1 Since its discovery, Bmi-1 has been implicated in a number of biological functions including development, cell cycle, DNA damage response (DDR), senescence, stem cell, self-renewal and cancer. Recently, Bmi-1 has proven to be MAPK13-IN-1 of significant clinical interest as it has been noted to be overexpressed in a number of diseases and malignancies. This review will seek to give a basic overview of Bmi-1, its functions, and its potential research and clinical implications. Bmi-1 protein The gene localizes on chromosome 10 (10p11.23) encodes for a 37?kDa protein composed of 326 amino acids.2, 3 Its protein structure is highly evolutionarily conserved, demonstrating considerable homology with the Mel-18 genea transcriptional repressor of and identified as transcriptional repressors of geneshomeotic genes that regulate morphogenesis and tissue differentiation.13 Consequently, PcG proteins have been studied in their potential connection to cancer stem cells. Like stem cells in healthy tissues, tumors appear to contain a small subset of cells that have the potential MAPK13-IN-1 to repopulate and affect transcriptional regulation patterns. Since PcG proteins play a role in transcriptional repression, it is hypothesized that they may be highly involved in stem cell renewal and cancer development.14 There are two multimeric PcG protein complexes: Polycomb repressor complex 1 (PRC1) and Polycomb repressor complex 2 (PRC2).3 As these complexes have been investigated, core functional components have been determined for both families of PcG proteins. In humans, MAPK13-IN-1 the canonical PRC1 is usually comprised of Bmi-1, RING1A/B, PCGF, CBX, and HPH, while the core PRC2 is comprised of EZH, SUZ12, and EED.15 (summarized in Table 1). As a part of PRC1, Bmi-1 interacts with RING1B via its own RING domain name and enhances the E3 ubiquitin ligase activity to ubiquitinate histone H2A.5 PRC2 operates as a histone transmethylase that mono-, di-, and trimethylates the Lys27 residue of histone H3.16 Traditionally, EED has only been associated with PRC2; however, a recent study suggests that EED plays an important role in both PRC1 and PRC2, and thus may potentially be a key coordinator in transcriptional regulation. 17 Table 1 Components of the PRC1 and PRC2 complexes. Tudor protein; WD40 C 40 residue tryptophan and aspartic acid repeat; YY C YinCYang. Mouse models Murine and human Bmi-1 display a high degree of similarity at the cDNA (92.4%) and at the protein level (98%), making mice the primary model organism for Bmi-1.2 A definitive study conducted by van der Lugt et?al, demonstrated that knockout mice are characterized by a survival rate of only 50% by the third day after birth.4 Additionally, knockout mice experienced increased frequency of illness, hematopoietic abnormalities in the liver and bone marrow, lymphoid abnormalities in the thymus and spleen, skeletal MAPK13-IN-1 defects, ataxic gait, and reduced density in cerebellum and neural layers.4 Hematopoietic cell counts in the knockout mice were reduced to roughly 30% of wild-type levels and continued to decrease as the mice aged. The majority of thymocytes in the knockout mice were immature, with total thymocyte levels being decreased to below 1%. the fetal cells developed relatively normally and only displayed severe defects with age. Despite the hematopoietic abnormalities, the red blood cell count and associated blood parameters did not significantly change in the knockout mice.18 A further study using knockout mice found that reactive oxygen species (ROS) increased in various cell populations, especially thymocytes. 19 In this study, the knockout thymocytes exhibited diminished oxidative capacity as well as reduced basal mitochondrial oxygen consumptionboth of which contributed to an enhanced DNA damage response (DDR).19 An interesting reporter study found that Bmi-1 Amfr is highly expressed in quiescent intestinal stem cells (ISCs). Self-renewal proteins Lgr5 and Bmi-1 were fluorescently tagged within mice ISCs and were studied before and after irradiation. Before irradiation, the Bmi-1 expressing ISCs were characterized as quiescent, while the Lgr5 ISCs were shown to be mitotically active. However, upon irradiation, the Lgr5 ISCs exhibited susceptibility and died out quickly; in contrast, the Bmi-1 ISCs displayed high resistance to irradiation and proliferated.