PIM1
Encyclopedia
Proto-oncogene serine/threonine-protein kinase Pim-1 is an enzyme
that in humans is encoded by the PIM1 gene
.
Pim-1 is a proto-oncogene which encodes for the serine/threonine kinase of the same name. The pim-1 oncogene was first described in relation to murine T-cell lymphoma
s, as it was the locus most frequently activated by the Moloney murine leukemia virus
. Subsequently, the oncogene has been implicated in multiple human cancers, including prostate cancer
, acute myeloid leukemia
and other hematopoietic
malignancies. Primarily expressed in spleen, thymus, bone marrow, prostate, oral epithelial
, hippocampus
and fetal liver cells, Pim-1 has also been found to be highly expressed in cell culture
s isolated from human tumors. Pim-1 is mainly involved in cell cycle
progression, apoptosis
and transcriptional
activation, as well as more general signal transduction
pathways.
. Direct binding of transcription factors STAT3
and STAT5
to the pim-1 promoter results in the transcription of pim-1. The pim-1 gene has been found to be conserved in dogs, cows, mice, rats, zebrafish and C. elegans
. Pim-1 deficient mice have been shown to be phenotypically normal, indicating that there is redundancy in the function of this kinase. In fact, sequence homology searches have shown that two other Pim-1-like kinases, Pim-2 and Pim-3, are structurally and functionally similar. Interestingly, the pim-1 gene encodes has multiple translation initiation sites, resulting in two proteins of 34 and 44kD.
signaling, and has been implicated in many signal transduction
pathways. Because Pim-1 translation is initiated by STAT3 and STAT5, its production is regulated by the cytokines that regulate the STAT pathway, or STAT factors. These include interleukin
s (IL-2, IL-3,IL-5, IL-6, IL-7, IL12, IL-15), prolactin, TNFα, EGF
and IFNγ
, among others. Interestingly, Pim-1 itself can bind to negative regulators of the JAK/STAT pathway, resulting in a negative feedback loop.
Although little is known about the post-transcriptional modifications of Pim-1, it has been hypothesized that Hsp90
is responsible for the folding and stabilization of Pim-1, although the exact mechanism has yet to be discovered. Furthermore, the serine/threonine phosphatase PP2 has been shown to degrade Pim-1.
with:
Other known substrates/binding partners of Pim-1 include proteins involved in transcription regulation (nuclear adaptor protein p100
, HP-1
, PAP-1
and TRAF2
/ SNX6
), and regulation of the JAK/STAT pathway (SOCS1
and SOCS3
). Furthermore, Pim-1 has been shown to be a cofactor for c-Myc
, a transcription factor
believed to regulate 15% of all genes, and their synergy has been in prostate tumorigenesis.
Pim-1 is able to phosphorylate many targets, including itself. Many of its targets are involved in cell cycle
regulation.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that in humans is encoded by the PIM1 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Pim-1 is a proto-oncogene which encodes for the serine/threonine kinase of the same name. The pim-1 oncogene was first described in relation to murine T-cell lymphoma
T-cell lymphoma
The T-cell lymphomas are the four types of lymphoma that affect T cells. These account for perhaps one in ten cases of non-Hodgkin lymphoma.They can be associated with Epstein Barr virus and Human T-cell leukemia virus-1.-Types:The four classes are:...
s, as it was the locus most frequently activated by the Moloney murine leukemia virus
Murine leukemia virus
The murine leukemia viruses are retroviruses named for their ability to cause cancer in murine hosts. Some MLVs may infect other vertebrates. MLVs include both exogenous and endogenous viruses...
. Subsequently, the oncogene has been implicated in multiple human cancers, including prostate cancer
Prostate cancer
Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...
, acute myeloid leukemia
Acute myeloid leukemia
Acute myeloid leukemia , also known as acute myelogenous leukemia, is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute...
and other hematopoietic
Haematopoiesis
Haematopoiesis is the formation of blood cellular components. All cellular blood components are derived from haematopoietic stem cells...
malignancies. Primarily expressed in spleen, thymus, bone marrow, prostate, oral epithelial
Epithelium
Epithelium is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. Epithelial tissues line the cavities and surfaces of structures throughout the body, and also form many glands. Functions of epithelial cells include secretion, selective...
, hippocampus
Hippocampus
The hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
and fetal liver cells, Pim-1 has also been found to be highly expressed in cell culture
Cell culture
Cell culture is the complex process by which cells are grown under controlled conditions. In practice, the term "cell culture" has come to refer to the culturing of cells derived from singlecellular eukaryotes, especially animal cells. However, there are also cultures of plants, fungi and microbes,...
s isolated from human tumors. Pim-1 is mainly involved in cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
progression, apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
and transcriptional
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
activation, as well as more general signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
pathways.
Gene
Located on chromosome 6 (6p21.2), the gene encompasses 5Kb of DNA, including 6 exons and 5 introns. Expression of Pim-1 has been shown to be regulated by the JAK/STAT pathwayJAK-STAT signaling pathway
The JAK-STAT signaling pathway transmits information from chemical signals outside the cell, through the cell membrane, and into gene promoters on the DNA in the cell nucleus, which causes DNA transcription and activity in the cell. The JAK-STAT system is a major signaling alternative to the second...
. Direct binding of transcription factors STAT3
STAT3
Signal transducer and activator of transcription 3 also known as STAT3 is a transcription factor which in humans is encoded by the STAT3 gene.- Function :The protein encoded by this gene is a member of the STAT protein family...
and STAT5
STAT5
STAT5 refers to two highly related proteins, STAT5A and STAT5B, which are encoded by separate genes, but are 90% identical at the amino acid level....
to the pim-1 promoter results in the transcription of pim-1. The pim-1 gene has been found to be conserved in dogs, cows, mice, rats, zebrafish and C. elegans
Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
. Pim-1 deficient mice have been shown to be phenotypically normal, indicating that there is redundancy in the function of this kinase. In fact, sequence homology searches have shown that two other Pim-1-like kinases, Pim-2 and Pim-3, are structurally and functionally similar. Interestingly, the pim-1 gene encodes has multiple translation initiation sites, resulting in two proteins of 34 and 44kD.
Protein structure
Human, murine and rat pim-1 contain 313 amino acids, and have a 94 – 97% amino acid identity. The active site of the protein, ranging from amino acids 38-290, is composed of several conserved motifs, including a glycine loop motif, a phosphate binding site and a proton acceptor site. Modification of the protein at amino acid 67 (lysine to methionine) results in the inactivation of the kinase.Activation and stabilization
Pim-1 is primarily involved in cytokineCytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...
signaling, and has been implicated in many signal transduction
Signal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
pathways. Because Pim-1 translation is initiated by STAT3 and STAT5, its production is regulated by the cytokines that regulate the STAT pathway, or STAT factors. These include interleukin
Interleukin
Interleukins are a group of cytokines that were first seen to be expressed by white blood cells . The term interleukin derives from "as a means of communication", and "deriving from the fact that many of these proteins are produced by leukocytes and act on leukocytes"...
s (IL-2, IL-3,IL-5, IL-6, IL-7, IL12, IL-15), prolactin, TNFα, EGF
Epidermal growth factor
Epidermal growth factor or EGF is a growth factor that plays an important role in the regulation of cell growth, proliferation, and differentiation by binding to its receptor EGFR...
and IFNγ
Interferon-gamma
Interferon-gamma is a dimerized soluble cytokine that is the only member of the type II class of interferons. This interferon was originally called macrophage-activating factor, a term now used to describe a larger family of proteins to which IFN-γ belongs...
, among others. Interestingly, Pim-1 itself can bind to negative regulators of the JAK/STAT pathway, resulting in a negative feedback loop.
Although little is known about the post-transcriptional modifications of Pim-1, it has been hypothesized that Hsp90
Hsp90
Hsp90 is a molecular chaperone and is one of the most abundant proteins expressed in cells. It is a member of the heat shock protein family, which is upregulated in response to stress...
is responsible for the folding and stabilization of Pim-1, although the exact mechanism has yet to be discovered. Furthermore, the serine/threonine phosphatase PP2 has been shown to degrade Pim-1.
Interactions
PIM1 has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with:
- CBX3CBX3Chromobox protein homolog 3 is a protein that in humans is encoded by the CBX3 gene.-Interactions:CBX3 has been shown to interact with PIM1, Ki-67, Lamin B receptor, CBX5 and CBX1....
, - CDC25ACDC25ACell division cycle 25 homolog A , also known as CDC25A, is a mammalian gene.-Interactions:CDC25A has been shown to interact with ASK1, Epidermal growth factor receptor, C-Raf, CHEK1, Cyclin E1, PIM1 and YWHAB.-Further reading:...
, - Heat shock protein 90kDa alpha (cytosolic), member A1,
- NFATC1NFATC1Nuclear factor of activated T-cells, cytoplasmic 1 is a protein that in humans is encoded by the NFATC1 gene.-Further reading:- External links :...
, - Nuclear mitotic apparatus protein 1Nuclear mitotic apparatus protein 1Nuclear mitotic apparatus protein 1 is a protein that in humans is encoded by the NUMA1 gene.-Interactions:Nuclear mitotic apparatus protein 1 has been shown to interact with PIM1, Band 4.1, GPSM2 and EPB41L1.-Further reading:...
, - P21P21p21 / WAF1 also known as cyclin-dependent kinase inhibitor 1 or CDK-interacting protein 1 is a protein that in humans is encoded by the CDKN1A gene located on chromosome 6 .- Function :...
, - SND1SND1Staphylococcal nuclease domain-containing protein 1 also known as 100 kDa coactivator or Tudor domain-containing protein 11 is a protein that in humans is encoded by the SND1 gene...
and - RELARELATranscription factor p65 is a protein that in humans is encoded by the RELA gene.-Interactions:RELA has been shown to interact with NFKBIB, ETHE1, NFKBIE, RFC1, TRIB3, CREB binding protein, Neutrophil cytosolic factor 1, Glucocorticoid receptor, MTPN, BRCA1, C-Fos, POU2F1, BTRC, TATA-binding...
.
Other known substrates/binding partners of Pim-1 include proteins involved in transcription regulation (nuclear adaptor protein p100
TPX2
Targeting protein for Xklp2 is a protein that in humans is encoded by the TPX2 gene.-Interactions:TPX2 has been shown to interact with Aurora A kinase.-Further reading:...
, HP-1
PTPN6
Tyrosine-protein phosphatase non-receptor type 6 is an enzyme that in humans is encoded by the PTPN6 gene.Also known as Src homology region 2 domain-containing phosphatase-1 .-Interactions:...
, PAP-1
RP9
Retinitis pigmentosa 9 , also known as RP9 or PAP-1, is a protein which in humans is encoded by the RP9 gene.- Function :...
and TRAF2
TRAF2
TNF receptor-associated factor 2 is a protein that in humans is encoded by the TRAF2 gene.-Interactions:TRAF2 has been shown to interact with BCL10, CD30, CFLAR, IKK2, MAP3K7IP2, CD137, Caveolin 1, CD27, TNFRSF13B, TANK-binding kinase 1, TRAF1, CD40, UBE2N, MAP3K14, MAP4K2, CASP8AP2, HIVEP3,...
/ SNX6
SNX6
Sorting Nexin 6 also known as SNX6 is a well-conserved membrane-associated protein belonging to the sorting nexin family that is a component of the retromer complex. The protein contains a coiled-coil domain at its C terminus and a PX domain at its N terminus. Binding to PIM1 causes translocation...
), and regulation of the JAK/STAT pathway (SOCS1
Suppressor of cytokine signaling 1
Suppressor of cytokine signaling 1 is a protein that in humans is encoded by the SOCS1 gene. SOCS1 orthologs have been identified in several mammals for which complete genome data are available.-Interactions:...
and SOCS3
SOCS3
Suppressor of cytokine signaling 3 is a protein that in humans is encoded by the SOCS3 gene.-Interactions:SOCS3 has been shown to interact with PTPN11, Glycoprotein 130, Erythropoietin receptor, Janus kinase 2, RAS p21 protein activator 1 and Insulin-like growth factor 1 receptor.-Regulation:There...
). Furthermore, Pim-1 has been shown to be a cofactor for c-Myc
Myc
Myc is a regulator gene that codes for a transcription factor. In the human genome, Myc is located on chromosome 8 and is believed to regulate expression of 15% of all genes through binding on Enhancer Box sequences and recruiting histone acetyltransferases...
, a transcription factor
Transcription factor
In molecular biology and genetics, a transcription factor is a protein that binds to specific DNA sequences, thereby controlling the flow of genetic information from DNA to mRNA...
believed to regulate 15% of all genes, and their synergy has been in prostate tumorigenesis.
Pim-1 is able to phosphorylate many targets, including itself. Many of its targets are involved in cell cycle
Cell cycle
The cell cycle, or cell-division cycle, is the series of events that takes place in a cell leading to its division and duplication . In cells without a nucleus , the cell cycle occurs via a process termed binary fission...
regulation.
Activates
- Cdc25CCdc25Cdc25 is a dual-specificity phosphatase first isolated from the yeast Schizosaccharomyces pombe as a cell cycle defective mutant. As with other cell cycle proteins such as Cdc2 and Cdc4, the "cdc" in its name refers to "cell division cycle".Dual-specificity phosphatases are considered a sub-class...
(G1/S positive regulator): Activation results in increased G1G1 phaseThe G1 phase is a period in the cell cycle during interphase, before the S phase. For many cells, this phase is the major period of cell growth during its lifespan. During this stage new organelles are being synthesized, so the cell requires both structural proteins and enzymes, resulting in great...
→ SS phaseS-phase is the part of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Precise and accurate DNA replication is necessary to prevent genetic abnormalities which often lead to cell death or disease. Due to the importance, the regulatory pathways that govern this... - Cdc25CCdc25Cdc25 is a dual-specificity phosphatase first isolated from the yeast Schizosaccharomyces pombe as a cell cycle defective mutant. As with other cell cycle proteins such as Cdc2 and Cdc4, the "cdc" in its name refers to "cell division cycle".Dual-specificity phosphatases are considered a sub-class...
(G2/M positive regulator): Activation results in increased G2G2 phaseG2 phase is the 3rd and final subphase of Interphase in the cell cycle directly preceding Mitosis. It follows the successful completion of S phase, during which the cell’s DNA is replicated...
→ MMitosisMitosis is the process by which a eukaryotic cell separates the chromosomes in its cell nucleus into two identical sets, in two separate nuclei. It is generally followed immediately by cytokinesis, which divides the nuclei, cytoplasm, organelles and cell membrane into two cells containing roughly...
Deactivates
- Bad (Pro-apoptotic protein): Deactivation results in increased cell survival
- CKICyclin-dependent kinase inhibitor proteinA cyclin-dependent kinase inhibitor protein is a protein which inhibits cyclin-dependent kinase. Several function as tumor suppressor genes. Cell cycle progression is negatively controlled by cyclin-dependent kinases inhibitors . CDIs are involved in cell cycle arrest at the G1 phase.-Examples:...
(G1/S negative regulator): Deactivation results in increased G1 → S - C-TAK1MARK3MAP/microtubule affinity-regulating kinase 3 is an enzyme that in humans is encoded by the MARK3 gene.-Interactions:MARK3 has been shown to interact with Stratifin.-Further reading:...
(Cdc25C inhibitor): Deactivation results in increased G2 → M