Popivanova BK, Li YY, Zheng H, Omura K, Fujii C, Tsuneyama K, Mukaida NProto-oncogene, Pim-3 with serine/threonine kinase activity, is aberrantly expressed in human colon cancer cells and can prevent Bad-mediated apoptosis. Cancer Sci 98(3): 321-328

Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University 13-1 Takara-machi, Kanazawa 920-0934, Japan.
Cancer Science (Impact Factor: 3.52). 04/2007; 98(3):321-8. DOI: 10.1111/j.1349-7006.2007.00390.x
Source: PubMed


We previously observed that Pim-3 with serine/threonine kinase activity, was aberrantly expressed in malignant lesions of endoderm-derived organs, liver and pancreas. Because Pim-3 protein was not detected in normal colon mucosal tissues, we evaluated Pim-3 expression in malignant lesions of human colon, another endoderm-derived organ. Pim-3 was detected immunohistochemically in well-differentiated (43/68 cases) and moderately differentiated (23/41 cases) but not poorly differentiated colon adenocarcinomas (0/5 cases). Moreover, Pim-3 proteins were detected in adenoma (35/40 cases) and normal mucosa (26/111 cases), which are adjacent to adenocarcinoma. Pim-3 was constitutively expressed in SW480 cells and the transfection with Pim-3 short hairpin RNA promoted apoptosis. In the same cell line, a pro-apoptotic molecule, Bad, was phosphorylated at Ser(112) and Ser(136) sites of phosphorylation that are representative of its inactive form. Ser(112) but not Ser(136) phosphorylation in this cell line was abrogated by Pim-3 knockdown. Furthermore, in human colon cancer tissues, Pim-3 co-localized with Bad in all cases (9/9) and with phospho-Ser(112)Bad in most cases (6/9). These observations suggest that Pim-3 can inactivate Bad by phosphorylating its Ser(112) in human colon cancer cells and thus may prevent apoptosis and promote progression of human colon cancer.

Download full-text


Available from: Naofumi Mukaida
  • Source
    • "Although the contribution of Pim3 in mammalian development needs further investigation, its role as an oncogene is well documented. Aberrant Pim3 expression in cancer cells mediates its anti-apoptotic effects by phosphorylating Bad [38], [39]. This is potentially significant, since PPARγ is also highly expressed in many cancers [40] and therefore may play a role in inhibiting apoptosis via Pim3 expression. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The pathophysiology of obesity and type 2 diabetes mellitus is associated with abnormalities in endocrine signaling in adipose tissue and one of the key signaling affectors operative in these disorders is the nuclear hormone transcription factor peroxisome proliferator-activated receptor-γ (PPARγ). PPARγ has pleiotropic functions affecting a wide range of fundamental biological processes including the regulation of genes that modulate insulin sensitivity, adipocyte differentiation, inflammation and atherosclerosis. To date, only a limited number of direct targets for PPARγ have been identified through research using the well established pre-adipogenic cell line, 3T3-L1. In order to obtain a genome-wide view of PPARγ binding sites, we applied the pair end-tagging technology (ChIP-PET) to map PPARγ binding sites in 3T3-L1 preadipocyte cells.
    Full-text · Article · Feb 2009 · PLoS ONE
  • Source
    • "Degradation of ECM may also come about through the modulation of protease-sensitive regulatory networks involving other proteases and nonproteases such as annexin II present on the surface of cancer cells [41]. Other recently found enzymes produced by cancer cells are heparanase [42] and the AKT serine/threonine protein kinase [43]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The mechanisms whereby colorectal carcinomas invade the extracellular matrix remain elusive. In a series of studies on the growing edge of colorectal carcinomas, we found dilated neoplastic glands, some with a layer of flat tumor cells, and some lacking one or more groups of consecutive lining tumor cells (called glandular pores). Through the glandular pores, the retained glandular material was siphoned off directly into the juxtaposed extracellular matrix. The substances secreted by the tumor cells, rich in proteolytic enzymes, disrupted the anatomy of the extracellular matrix. To remodel the defective glands, the malignant cells, proliferating from the tip of the free borders of the pores, invade the enzymatically disrupted matrix to achieve glandular continuity. Sealing of these glandular flaws permits intraglandular accumulation of new proteolytic material, a mechanism that replicates a new wave of host invasion at the invading edge, thus ensuring stepwise but everlasting tumor progression in untreated patients. More recent findings indicated that the flat tumor cells at the advancing edge failed to express the proliferation marker Ki67 but overexpressed the mutated p53 protein. This paradoxic biologic behavior of tumor cells may be connected with the subsequent formation of glandular pores and strongly suggests that the arrested cell proliferation at the advancing tumor edge occurs independently of p53 mutation. Possibly, two independent molecular systems exist at the advancing edge of colonic carcinomas, one supervising cell proliferation and the other actively transferring the mutated p53 protein to daughter cells.
    Full-text · Article · Feb 2008 · International journal of clinical and experimental pathology
  • Source
    • "There is insufficient information available to generate a clear hypothesis about the function of Egr genes in the SCN. Pim3 is a serine/threonine protein kinase that has anti-apoptotic functions in a variety of tissues [18,19], but its role in neurons has not been investigated. In contrast, the known functions of Gadd45b and Tiparp suggest potential connections to SCN function. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The transmission of information about the photic environment to the circadian clock involves a complex array of neurotransmitters, receptors, and second messenger systems. Exposure of an animal to light during the subjective night initiates rapid transcription of a number of immediate-early genes in the suprachiasmatic nucleus of the hypothalamus. Some of these genes have known roles in entraining the circadian clock, while others have unknown functions. Using laser capture microscopy, microarray analysis, and quantitative real-time PCR, we performed a comprehensive screen for changes in gene expression immediately following a 30 minute light pulse in suprachiasmatic nucleus of mice. The results of the microarray screen successfully identified previously known light-induced genes as well as several novel genes that may be important in the circadian clock. Newly identified light-induced genes include early growth response 2, proviral integration site 3, growth-arrest and DNA-damage-inducible 45 beta, and TCDD-inducible poly(ADP-ribose) polymerase. Comparative analysis of promoter sequences revealed the presence of evolutionarily conserved CRE and associated TATA box elements in most of the light-induced genes, while other core clock genes generally lack this combination of promoter elements. The photic signalling cascade in the suprachiasmatic nucleus activates an array of immediate-early genes, most of which have unknown functions in the circadian clock. Detected evolutionary conservation of CRE and TATA box elements in promoters of light-induced genes suggest that the functional role of these elements has likely remained the same over evolutionary time across mammalian orders.
    Full-text · Article · Feb 2007 · BMC Neuroscience
Show more