Selten, G. et al. The primary structure of the putative oncogene pim-1 shows extensive homology with protein kinases. Cell 46, 603-611
The Salk Institute P. O. Box 85800 San Diego, California 92138 USA Cell
(Impact Factor: 32.24).
09/1986; 46(4):603-11. DOI: 10.1016/0092-8674(86)90886-X
We have shown previously that the putative oncogene pim-1 is frequently activated by provirus insertion in murine leukemia virus-induced T cell lymphomas. Here we describe the structure of the pim-1 gene as determined by sequencing genomic and cDNA clones. The gene has an open reading frame, encoding a protein of 313 amino acids, extending over six exons and preceded and followed by stop codons in all reading frames. Proviruses always integrate outside the protein-encoding domain, showing a high preference for a small region in the 3'-terminal exon; integration in the 3' exon results in relatively high levels of pim-1 mRNA. Computer search reveals homology between pim-1 and protein kinases: all the domains characteristic of protein kinases are conserved in the pim-1 amino acid sequence. The highest homologies were observed with the protein-serine kinases.
Available from: Perez Marco
- "Elevated levels of Pim1 kinase were first reported in human leukemia and lymphomas , , . Recently, Pim1 was found to be increased in solid tumors, including pancreatic and prostate cancers, squamous cell carcinoma, gastric, colorectal and liver carcinomas , , and liposarcoma . "
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ABSTRACT: The Pim proteins are a family of highly homologous protein serine/threonine kinases that have been found to be overexpressed in cancer. Elevated levels of Pim1 kinase were first discovered in human leukemia and lymphomas. However, more recently Pim1 was found to be increased in solid tumors, including pancreatic and prostate cancers, and has been proposed as a prognostic marker. Although the Pim kinases have been identified as oncogenes in transgenic models, they have weak transforming abilities on their own. However, they have been shown to greatly enhance the ability of other genes or chemical carcinogens to induce tumors. To explore the role of Pim1 in prostate cancer, we generated conditional Pim1 transgenic mice, expressed Pim1 in prostate epithelium, and analyzed the contribution of PIM1 to neoplastic initiation and progression. Accordingly, we explored the effect of PIM1 overexpression in 3 different settings: upon hormone treatment, during aging, and in combination with the absence of one Pten allele. We have found that Pim1 overexpression increased the severity of mouse prostate intraepithelial neoplasias (mPIN) moderately in all three settings. Furthermore, Pim1 overexpression, in combination with the hormone treatment, increased inflammation surrounding target tissues leading to pyelonephritis in transgenic animals. Analysis of senescence induced in these prostatic lesions showed that the lesions induced in the presence of inflammation exhibited different behavior than those induced in the absence of inflammation. While high grade prostate preneoplastic lesions, mPIN grades III and IV, in the presence of inflammation did not show any senescence markers and demonstrated high levels of Ki67 staining, untreated animals without inflammation showed senescence markers and had low levels of Ki67 staining in similar high grade lesions. Our data suggest that Pim1 might contribute to progression rather than initiation in prostate neoplasia.
Available from: Remziye Nalcacioglu
- "In this study , the possible change of the APE motif to TLE is clearly explained . It is found that this motif within published kinase sequences reveals some heterogeneity and demon - strates that the final glutamic acid is the only invariant residue ( Selten et al . 1986 ) . Replacement of alanine with other neutral residues ( glycine , leucine and proline ) has been observed . Alanine ( neutral ) , leucine , and isoleucine ( nonpolar ) have been found as substitutes for the central proline . Subdomain IX is thought to be placed at the sequences 206DIESLM211 , but may also include the 212YNIIEWYSG220 se"
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ABSTRACT: The Amsacta moorei entomopoxvirus (AMEV) genome has 279 open reading frames (ORFs) among which is the AMV197, composed of 900 nt and potentially
encoding a protein of 299 amino acids. Sequence-derived amino acid analysis suggested it to be a serine/threonine protein
kinase (PK) having conserved PK and serine/threonine PK domains. For transcriptional analysis of the AMV197 pk gene, Ld652 cells were infected with AMEV and mRNA was isolated at different times thereafter. RT–PCR analysis indicated
that the transcription of the AMV197 pk gene started at 4h post infection (h p.i.) and continued to be expressed through 24h p.i. Infection of Ld cells in the
presence of Ara-C (inhibits DNA replication), followed by RT–PCR showed that AMV197 pk is transcribed as an early gene. Transcription was initiated at 54 nt upstream of the translation start site. The vaccinia
virus early promoter element G was also found at the correct position (−21) in the AMV197 pk gene. Rapid amplification of the 3′ ends of the AMV197 pk transcript showed that there are two polyadenylation start points. They are located at 22 and 32 nucleotides downstream of
translation stop site. Also, the translational stop site and poly (A) signal of AMV197 pk are overlapped. The termination signal TTTTTGT sequence of vaccinia virus early genes was found just upstream of the 3′ end
of AMV197 pk gene. Conserved amino acid subdomains of the AMV197 PK were found by sequence comparisons with PK’s from other organisms.
Analysis of the protein sequence of AMV197 pk gene reveals close identity with PK genes of other organisms.
Amsacta moorei entomopoxvirus (AMEV)-Protein kinase-Transcriptional analysis
Available from: Andrew Macdonald
- "Pim-1 was first identified as an oncogenic gene in murine T-cell lymphomas, which became activated after pro-viral insertion in the 3'UTR of the Pim-1 gene . Insertion in this region stabilised the mRNA for Pim-1 thus up-regulating the protein . Over-expression of the Pim-1 gene in B and T cells in transgenic mice resulted in a high level of lymphoma development in these mice, confirming the oncogenic properties of this protein [5,6]. "
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ABSTRACT: Pim-1, 2 and 3 are a group of enzymes related to the calcium calmodulin family of protein kinases. Over-expression of Pim-1 and Pim-2 in mice promotes the development of lymphomas, and up-regulation of Pim expression has been observed in several human cancers.
Here we show that the pim kinases are constitutively active when expressed in HEK-293 cells and are able to phosphorylate the Bcl-2 family member Bad on three residues, Ser112, Ser136 and Ser155 in vitro and in cells. In vitro mapping showed that Pim-2 predominantly phosphorylated Ser112, while Pim-1 phosphorylated Ser112, but also Ser136 and Ser155 at a reduced rate compared to Ser112. Pim-3 was found to be the least specific for Ser112, and the most effective at phosphorylating Ser136 and Ser155. Pim-3 was also able to phosphorylate other sites in Bad in vitro, including Ser170, another potential in vivo site. Mutation of Ser136 to alanine prevented the phosphorylation of Ser112 and Ser155 by Pim kinases in HEK-293 cells, suggesting that this site must be phosphorylated first in order to make the other sites accessible. Pim phosphorylation of Bad was also found to promote the 14-3-3 binding of Bad and block its association with Bcl-XL.
All three Pim kinase family members predominantly phosphorylate Bad on Ser112 and in addition are capable of phosphorylating Bad on multiple sites associated with the inhibition of the pro-apoptotic function of Bad in HEK-293 cells. This would be consistent with the proposed function of Pim kinases in promoting cell proliferation and preventing cell death.
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