| MSI2 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | MSI2 , MSI2H, musashi RNA binding protein 2, Musashi2, Musashi-2 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 607897; MGI: 1923876; HomoloGene: 62199; GeneCards: MSI2; OMA:MSI2 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Musashi-2, also known as Musashi RNA binding protein 2, is a protein that in humans is encoded by the MSI2 gene. [5] Like its homologue musashi-1 (MSI1), it is an RNA-binding protein involved in stemness.
There are two homologue genes found in mammals, called musashi1 (MSI1) and musashi-2 (MSI2). Musashi-2 is an RNA-binding protein expressed in neuronal progenitor cells, including stem cells, and both normal and leukemic blood cells. [6] [7]
Musashi-2 also appears to be expressed in stem cells and in a wide variety of tissues, including the bulge region of the hair follicle, immature pancreatic β-cells and neural progenitor cells. [6] Amongst the last ones, MSI2 is expressed in early stages of development, in the ventricular and subventricular zone, [8] in cells of the astrocyte lineage. It was there that it was first discovered. [6] Within the hematopoietic system, MSI2 is highly expressed in the most primitive progenitors, [6] [9] in stem cell compartments, [7] and its overexpression has been found in myeloid leukemia cell lines. [7] In neural cell lines, MSI2 protein, as well as its homologue MSI1, is exclusively located in the cytoplasm. [8]
In humans, the MSI2 gene is located in chromosome 17q23.2. [10] and has a sequence length of 1,414bp of which 987bp are encoded. [11] In mice, MSI2 has been found to be in 11qB5-C [8] and BC169841 in the African clawed frog (Xenopus laevis). [9] There are two different isoforms of MSI2 expressed by embryonic stem cells that result from alternative splicing, isoform 1 and isoform 2. The first one is the larger canonical isoform, and the second one is the shorter, splice-variant Isoform.
This gene encodes an RNA-binding protein that is a member of the Musashi protein family. The encoded protein is translational regulator that targets genes involved in development and cell cycle regulation. Mutations in this gene are associated with poor prognosis in certain types of cancers. This gene has also been shown to be rearranged in certain cancer cells. The first musashi (abbreviation MSI) gene was first discovered in Drosophila and then later identified in other eukaryotic species.
MSI2 is involved in organismal development. [12] As with the rest of Musashi family RNA-binding proteins, MSI2 is linked to tissue stem cells and has an influence in asymmetric cell division, germ and somatic stem cell function and cell fate determination in a variety of tissues. [7]
As an RNA-binding protein, MSI2 is acts as a translational inhibitor. [9] Through this molecular mechanism, MSI2 contributes in more than one vital aspect, as in the development of the nervous system, regulation of the Hematopoietic stem cell (HSC) compartment, or the self-renewal and pluripotency of embryonic stem cells. MSI2 takes part in a high number of pathways related to the self-renewal of some stem cells. However, it is not only focused in one specific type. Depending on the tissue where it is located, it develops different functions.
MSI2 belongs to the RNA-processing group of proteins which are associated with the transcription factor SOX2 during the early stages of differentiation. SOX2 is known to be essential during embryogenesis and in the self-renewal and pluripotency of embryonic stem cells. MSI2 has a high influence on it too, since the gain or loss of self-renewal capacity and the extent of differentiation depends on MSI2 levels. Although both of the isoforms of this protein are needed to the maintenance of the self-renewal, they are different on a functional way and they play different roles in some aspects of the process. For example, only isoform 1 expression is related to the cloning efficiency of embryonic stem cells. [12]
In a similar way to MSI1, MSI2 is also active in the proliferation of pluripotent neural precursors cells of the embryo, during which both MSI1 and MSI2 are strongly co-expressed. Moreover, MSI1 and MSI2 regulate the multiplication and maintenance of a specific group inside of neural precursors cells: CNS (central neural system) stem cells populations. Therefore, MSI2 plays a significant role in the development and maintenance of CNS stem cells through post-transcriptional gene regulation. [7]
MSI2 is present in blood cells, in which its expression is situated in the hematopoietic system, more commonly in the most primitive cells. These are the LSK cells, which are composed by long-term hematopoietic stem cells (LT-HSCs), short-term HSCs (ST-HCSs) and multipotent progenitors (MPPs). [6]
Self-renewal and differentiation processes in hematopoietic stem cells need to be highly regulated in order to maintain homeostasis and to avoid the growing of blood cell malignancies. It is this point is where Musashi-2 interferes. [9] Therefore, MSI2’s function in HSCs consists of regulating their proliferation and differentiation. Therefore, a decreasing on the level of MSI2 induces a reduction in the number of more primitive progenitors of HSCs. [6]
As Musashi-2 is involved in the generation of hematopoietic cells, it is also linked with cancer pathologies:
It has been found that MSI2 plays an important role in myeloid leukemia. In both of chronic myelogenous leukemia (CML) and acute myeloid leukemia (AML), MSI2 regulates hematopoietic stem cell proliferation and does not allow the differentiation of its gene expression. [7]
Chronic myelogenous leukemia (CML) progresses from the initial phase, where differentiated myeloid cells are accumulated, to the accelerated phase, where the expansion of these cells increases, and it ends with the blast crisis phase. It has been found that MSI2 participates together with BCR-ABL gene to stimulate the progress to the aggressive phase. [7] The first evidence to consider its role in this phase is its high concentration compared with the first phase of the disease. One of the functions of the MSI2 is to regulate the expression of NUMB, causing its inhibition. [13] Therefore, the function of the MSI2 in this disease is being studied together with Numb expression. However, while Numb is overexpressed during the chronic phase and decreases in the blast one, Musashi starts to be overexpressed in the last fatal phase of CML. [14] The high expression of MSI2 interrupts the cellular differentiation and allows the expansion of immature leukemic cells causing the progress to the deadly phase. [14]
As acute myeloid leukemia (AML) has a similar behavior to the aggressive phase of the CML, MSI2’s role is similar there as well. It has been found that MSI2 is overexpressed in this type of leukemia and its activity is related with Numb consequently. Moreover, the high expression of MSI2 is related with a poor clinical outcome. [6] In order to prove this, it has been demonstrated that with MSI’s knockdown leads to a rising apoptosis and differentiation and to a decreasing proliferation. [14] As a result, patients that develop leukemia without a high expression of MSI2 have a better prognostic.
MIS2 is a potential cancer biomarker as well as a drug target. [15]
Haematopoiesis is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells. In a healthy adult human, roughly ten billion to a hundred billion new blood cells are produced per day, in order to maintain steady state levels in the peripheral circulation.
Cellular differentiation is the process in which a stem cell changes from one type to a differentiated one. Usually, the cell changes to a more specialized type. Differentiation happens multiple times during the development of a multicellular organism as it changes from a simple zygote to a complex system of tissues and cell types. Differentiation continues in adulthood as adult stem cells divide and create fully differentiated daughter cells during tissue repair and during normal cell turnover. Some differentiation occurs in response to antigen exposure. Differentiation dramatically changes a cell's size, shape, membrane potential, metabolic activity, and responsiveness to signals. These changes are largely due to highly controlled modifications in gene expression and are the study of epigenetics. With a few exceptions, cellular differentiation almost never involves a change in the DNA sequence itself. Metabolic composition, however, gets dramatically altered where stem cells are characterized by abundant metabolites with highly unsaturated structures whose levels decrease upon differentiation. Thus, different cells can have very different physical characteristics despite having the same genome.
Oct-4, also known as POU5F1, is a protein that in humans is encoded by the POU5F1 gene. Oct-4 is a homeodomain transcription factor of the POU family. It is critically involved in the self-renewal of undifferentiated embryonic stem cells. As such, it is frequently used as a marker for undifferentiated cells. Oct-4 expression must be closely regulated; too much or too little will cause differentiation of the cells.
Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within the (midgestational) aorta-gonad-mesonephros region, through a process known as endothelial-to-hematopoietic transition. In adults, haematopoiesis occurs in the red bone marrow, in the core of most bones. The red bone marrow is derived from the layer of the embryo called the mesoderm.
Homeobox protein NANOG(hNanog) is a transcriptional factor that helps embryonic stem cells (ESCs) maintain pluripotency by suppressing cell determination factors. hNanog is encoded in humans by the NANOG gene. Several types of cancer are associated with NANOG.
Leukemia inhibitory factor, or LIF, is an interleukin 6 class cytokine that affects cell growth by inhibiting differentiation. When LIF levels drop, the cells differentiate.
Stem cell factor is a cytokine that binds to the c-KIT receptor (CD117). SCF can exist both as a transmembrane protein and a soluble protein. This cytokine plays an important role in hematopoiesis, spermatogenesis, and melanogenesis.
Forkhead box protein P1 is a protein that in humans is encoded by the FOXP1 gene. FOXP1 is necessary for the proper development of the brain, heart, and lung in mammals. It is a member of the large FOX family of transcription factors.
Runt-related transcription factor 1 (RUNX1) also known as acute myeloid leukemia 1 protein (AML1) or core-binding factor subunit alpha-2 (CBFA2) is a protein that in humans is encoded by the RUNX1 gene.
Homeobox protein Hox-A9 is a protein that in humans is encoded by the HOXA9 gene.
SRY -box 2, also known as SOX2, is a transcription factor that is essential for maintaining self-renewal, or pluripotency, of undifferentiated embryonic stem cells. Sox2 has a critical role in maintenance of embryonic and neural stem cells.
ERG is an oncogene. ERG is a member of the ETS family of transcription factors. The ERG gene encodes for a protein, also called ERG, that functions as a transcriptional regulator. Genes in the ETS family regulate embryonic development, cell proliferation, differentiation, angiogenesis, inflammation, and apoptosis.
Homeobox protein Hox-B6 is a protein that in humans is encoded by the HOXB6 gene.
MDS1 and EVI1 complex locus protein EVI1 (MECOM) also known as ecotropic virus integration site 1 protein homolog (EVI-1) or positive regulatory domain zinc finger protein 3 (PRDM3) is a protein that in humans is encoded by the MECOM gene. EVI1 was first identified as a common retroviral integration site in AKXD murine myeloid tumors. It has since been identified in a plethora of other organisms, and seems to play a relatively conserved developmental role in embryogenesis. EVI1 is a nuclear transcription factor involved in many signaling pathways for both coexpression and coactivation of cell cycle genes.
Sal-like protein 4(SALL4) is a transcription factor encoded by a member of the Spalt-like (SALL) gene family, SALL4. The SALL genes were identified based on their sequence homology to Spalt, which is a homeotic gene originally cloned in Drosophila melanogaster that is important for terminal trunk structure formation in embryogenesis and imaginal disc development in the larval stages. There are four human SALL proteins with structural homology and playing diverse roles in embryonic development, kidney function, and cancer. The SALL4 gene encodes at least three isoforms, termed A, B, and C, through alternative splicing, with the A and B forms being the most studied. SALL4 can alter gene expression changes through its interaction with many co-factors and epigenetic complexes. It is also known as a key embryonic stem cell (ESC) factor.
ID4 is a protein coding gene. In humans, it encodes the protein known as DNA-binding protein inhibitor ID-4. This protein is known to be involved in the regulation of many cellular processes during both prenatal development and tumorigenesis. This is inclusive of embryonic cellular growth, senescence, cellular differentiation, apoptosis, and as an oncogene in angiogenesis.
RNA-binding protein Musashi homolog 1 also known as Musashi-1 is a protein that in humans is encoded by the MSI1 gene.
BAALC is a gene that codes for the brain and acute leukemia cytoplasmic protein. The official symbol (BAALC) and official name is maintained by the HGNC. The function of BAALC is not fully understood yet, but has been suggested to have synaptic roles involving the post synaptic lipid raft. Lipid rafts are microdomains that are enriched with cholesterol and sphingolipids, lipid raft functions include membrane trafficking, signal processing, and regulation of the actin cytoskeleton. The postsynaptic lipid raft possesses many proteins and is one of the major sites for signal processing and postsynaptic density (PSD). Along with its involvement in the post synaptic lipid rafts, BAALC expression has been associated with Acute Lymphoblastic Leukemia and Acute Myeloid Leukemia.
Stem cell markers are genes and their protein products used by scientists to isolate and identify stem cells. Stem cells can also be identified by functional assays. Below is a list of genes/protein products that can be used to identify various types of stem cells, or functional assays that do the same. The initial version of the list below was obtained by mining the PubMed database as described in
AI-10-49 is a small molecule inhibitor of leukemic oncoprotein CBFβ-SMHHC developed by the laboratory of John Bushweller with efficacy demonstrated by the laboratories of Lucio H. Castilla and Monica Guzman. AI-10-49 allosterically binds to CBFβ-SMMHC and disrupts protein-protein interaction between CBFβ-SMMHC and tumor suppressor RUNX1. This inhibitor is under development as an anti-leukemic drug.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
