Ferron M, Vacher JCharacterization of the murine Inpp4b gene and identification of a novel isoform. Gene 376:152-161
Institut de recherches cliniques de Montreal, 110 av. des Pins O., Montreal, Qc, Canada. Gene
(Impact Factor: 2.14).
08/2006; 376(1):152-61. DOI: 10.1016/j.gene.2006.02.022
Inositol polyphosphate phosphatases and phosphoinositides second messengers have been associated with major cellular functions as growth, differentiation, apoptosis, protein trafficking and motility. To characterize the role of inositol phosphatases in cell physiology, we have isolated the mouse Inositol polyphosphate 4-phosphatase type II (Inpp4b) cDNA. The murine Inpp4b locus was mapped on chromosome 8 in a synthenic region of the human 4q27-31 interval between Il-15 and Usp38. The mouse Inpp4b proteins, alpha and beta isoforms, encoded by this locus contained 927 and 941 amino acids respectively with a consensus phosphatase catalytic site and a conserved C2 domain that are highly similar with the human and rat homologues. Interestingly, we characterized a novel shorter isoform of Inpp4balpha resulting from an alternative translation initiation site and exon 5 skipping. Inpp4b C2 domain interacted with preferential affinity to phosphatidic acid and phosphatidylinositol 3,4,5-triphosphate (PI(3,4,5)P(3)) lipids. While analysis of Inpp4b transcript and protein expression demonstrated a broad tissue distribution for the alpha isoform, as for the paralogue Inpp4aalpha and beta isoforms, it also displayed a limited hematopoietic lineage distribution whereas the Inpp4bbeta isoform had a highly restricted pattern. Importantly, the Inpp4bbeta localized to the Golgi apparatus whereas Inpp4balpha was mainly cytosolic, suggesting a different cellular function for this isoform. Together our characterization of the murine Inpp4b gene expression pattern, cellular sublocalization and interacting lipids support highly specific function for individual Inpp4 phosphatase proteins.
Available from: PubMed Central
- "A total of 74 CpG sites spanning approximately 717-bp on the 5'CpG island of INPP4B were analyzed by bisulfite sequencing. This region covered the critical transcriptional regulatory domains sufficient for INPP4B expression in epithelial cells . The PCR primers for bisulfite sequencing and MSP assay are listed in Table S1. "
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ABSTRACT: Nasopharyngeal carcinoma (NPC) is a common viral-associated neoplasm in which multiple signaling cascades are interfered with by Epstein-Bar virus (EBV) latent proteins and various genetic alterations. Aside from the previously reported PIK3CA amplification, we examined the role of INPP4B, a negative regulator of the PI3K/AKT signaling pathway in the development of NPC. By RT-PCR and Western blotting, we revealed that the expression of INPP4B was down-regulated in all five established EBV-positive tumor lines. While INPP4B was consistently expressed in normal nasopharyngeal epithelial cells, downregulation of INPP4B was found in 32/65 (49.2%) of primary tumors by immunohistochemistry. Furthermore, our study also demonstrated the hypermethylation of the 5'CpG island of INPP4B in the tumors in which INPP4B transcription was downregulated. Notably, the re-expression of INPP4B was detected in the NPC cells treated with the demethylation agent (5-aza-2'deoxycytidine). Our study showed that promoter hypermethylation was the major mechanism for transcriptional silencing of INPP4B in NPC. Furthermore, restoration of INPP4B expression significantly suppressed PI3K/AKT downstream signals in the NPC C666-1 cells. In vivo growth inhibition was clearly demonstrated in the tumor cells stably expressing INPP4B. The findings indicate that epigenetic inactivation of INPP4B is one of the key mechanisms in activating PI3K/AKT signaling cascade and playing a role in the tumorigenesis of NPC.
PLoS ONE 08/2014; 9(8):e105163. DOI:10.1371/journal.pone.0105163 · 3.23 Impact Factor
Available from: nature.com
- "existence of INPP4B splice variants (INPP4Ba and INPP4Bb; Norris et al., 1997; Ferron and Vacher, 2006), and a shorter isoform of murine INPP4B (INPP4Bas; Ferron and Vacher, 2006) have been reported, showing differences in tissue distribution for individual INPP4 phosphatase proteins. Additional studies are needed for further characterization; however, our results demonstrate that INPP4B-specific depletion of the 85- kDa protein form correlates with PI3K pathway activation and a more aggressive phenotype in melanoma cells. "
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ABSTRACT: The PI3K pathway is deregulated in a significant proportion of melanomas, and PI3K pathway activation in combination with constitutively active MAPK signaling shows synergistic effects in the process of melanoma tumorigenesis. Recently, a tumor suppressor function for the lipid phosphatase INPP4B has been described in breast and prostate cancer with impact on PI3K signaling output. Given the importance of PI3K pathway activity for melanoma formation and growth, we aimed to assess the role of INPP4B in melanocytic tumors. Our studies suggest that decreased INPP4B expression is an event correlating with aggressive melanocytic neoplasms in native tumors. We further demonstrate that INPP4B regulates PI3K/Akt signaling and exerts a tumor suppressor effect in melanocytic cells, impacting on the proliferative, invasive and tumorigenic capacity of the melanoma phenotype. INPP4B expression in melanocytic neoplasms may therefore have potential as a biomarker for disease progression and as a modulator for the prediction of treatment outcome.Journal of Investigative Dermatology accepted article preview online, 28 November 2013. doi:10.1038/jid.2013.511.
Journal of Investigative Dermatology 11/2013; 134(5). DOI:10.1038/jid.2013.511 · 7.22 Impact Factor
Available from: sciencedirect.com
- "5 ) embryos ( Ferron and Vacher , 2006 ) . The two main Inpp4b transcripts , Inpp4ba and Inpp4bb are produced by alternative splicing of the 3 ' end of Inpp4b and are translated into the INPP4Ba and INPP4Bb proteins respectively ( Ferron and Vacher , 2006 ) . A comparison of Inpp4b transcript levels was performed among Tgkd / Tgkd , Tgkd ( mat ) / þ ( maternal inheritance ) , Tgkd ( pat ) / þ ( paternal inheritance ) and wild - type E13 . "
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ABSTRACT: Teratomas are a unique class of tumors composed of ecto-, meso- and endodermal tissues, all foreign to the site of origin. In humans, the most common teratoma is the ovarian teratoma. Not much is known about the molecular and genetic etiologies of these tumors. Female carriers of the Tgkd transgene are highly susceptible to developing teratomas. Ovaries of Tgkd/+ hemizygous female mice exhibit defects in luteinization, with numerous corpora lutea, some of which contain central trapped, fully-grown oocytes. Genetically, Tgkd teratomas originate from mature oocytes that have completed meiosis I, suggesting that Tgkd teratomas originate from these trapped oocytes. The insertion of Tgkd 3' of the Inpp4b gene is associated with decreased expression of Inpp4b and changes in intracellular PI3 Kinase/AKT signaling in follicular granulosa cells. Because Inpp4b is not expressed in fully-grown wild-type or Tgkd oocytes, these findings suggest that hyperactivation of the PI3K/AKT pathway caused by the decrease in INPP4B in granulosa cells promotes an ovarian environment defective in folliculogenesis and conducive to teratoma formation.
Developmental Biology 10/2012; 373(1). DOI:10.1016/j.ydbio.2012.10.011 · 3.55 Impact Factor
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