PIM1

Proto-oncogene serine/threonine-protein kinase Pim-1 is an is_associated_with::enzyme that in humans is encoded by the PIM1 is_associated_with::gene.

Pim-1 is a proto-oncogene which encodes for the is_associated_with::serine/threonine kinase of the same name. The pim-1 oncogene was first described in relation to murine is_associated_with::T-cell lymphomas, as it was the locus most frequently activated by the Moloney is_associated_with::murine leukemia virus. Subsequently, the oncogene has been implicated in multiple human cancers, including is_associated_with::prostate cancer, is_associated_with::acute myeloid leukemia and other hematopoietic malignancies. Primarily expressed in spleen, thymus, bone marrow, prostate, oral epithelial, is_associated_with::hippocampus and fetal liver cells, Pim-1 has also been found to be highly expressed in is_associated_with::cell cultures isolated from human tumors. Pim-1 is mainly involved in is_associated_with::cell cycle progression, is_associated_with::apoptosis and transcriptional activation, as well as more general is_associated_with::signal transduction 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 pathway. Direct binding of transcription factors is_associated_with::STAT3 and is_associated_with::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. 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 is_associated_with::cytokine signaling, and has been implicated in many is_associated_with::signal transduction pathways. Because Pim-1 transcription is initiated by STAT3 and STAT5, its production is regulated by the cytokines that regulate the STAT pathway, or STAT factors. These include is_associated_with::interleukins (IL-2, IL-3,IL-5, IL-6, IL-7, IL12, IL-15), prolactin, TNFα, EGF and IFNγ, among others. 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 is_associated_with::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.

Interactions
PIM1 has been shown to interact with:


 * is_associated_with::CBX3,
 * is_associated_with::CDC25A,
 * is_associated_with::Heat shock protein 90kDa alpha (cytosolic), member A1,
 * is_associated_with::NFATC1,
 * is_associated_with::Nuclear mitotic apparatus protein 1,
 * is_associated_with::P21,
 * is_associated_with::SND1 and
 * is_associated_with::RELA.

Other known substrates/binding partners of Pim-1 include proteins involved in transcription regulation (nuclear adaptor protein p100, HP-1, PAP-1 and is_associated_with::TRAF2 / is_associated_with::SNX6), and regulation of the JAK/STAT pathway (SOCS1 and is_associated_with::SOCS3). Furthermore, Pim-1 has been shown to be a cofactor for c-Myc, a is_associated_with::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 is_associated_with::cell cycle regulation.

Activates

 * Cdc25C	(G1/S positive regulator): Activation results in increased G1 → S
 * Cdc25C	(G2/M positive regulator): Activation results in increased G2 → M

Deactivates

 * Bad (Pro-apoptotic protein): Deactivation results in increased cell survival
 * CKI (G1/S negative regulator): Deactivation results in increased G1 → S
 * C-TAK1 (Cdc25C inhibitor): Deactivation results in increased G2 → M

Clinical implications
Pim-1 is directly involved in the regulation of cell cycle progression and apoptosis, and has been implicated in numerous cancers including prostate cancer, Burkitt’s lymphoma and oral cancer, as well as numerous hematopoietic lymphomas. Single nucleotide polymorphisms in the Pim-1 gene have been associated with increased risk for lung cancer in Korean patients, and have also been found in diffuse large cell lymphomas.