دانلود رایگان مقاله IPMK: رگولاتور همه کاره حوادث علامت دهی هسته ای

Abstract

Inositol-derived metabolites (e.g., phosphoinositides and inositol polyphosphates) are key second messengers that are essential for controlling a wide range of cellular events. Inositol polyphosphate multikinase (IPMK) exhibits complex catalytic activities that eventually yield water-soluble inositol polyphosphates (e.g., IP4 and IP5) and lipid-bound phosphatidylinositol 3,4,5-trisphosphate. A series of recent studies have suggested that IPMK may be a multifunctional regulator in the nucleus of mammalian cells. In this review, we highlight the novel modes of action of IPMK in transcriptional and epigenetic regulation, and discuss its roles in physiology and disease.

5. Concluding

remarks The idea that inositol polyphosphates and IPMK control transcription, which was introduced in 2000 and based on studies performed in Saccharomyces cerevisiae, is now widely accepted and has been broadly extended to various nuclear events in mammalian cells (Odom et al., 2000). The findings discussed in this review clearly suggest that mammalian IPMK and/or its catalytic products play multiple functions in the nucleus, as shown by the following lines of evidence: (i) As a nuclear PI3- kinase, IPMK was identified as a critical enzyme that produces ALY-activating PIP3, thereby promoting the export of specific nuclear mRNAs (e.g., those encoding DNA damage-sensitive recombination proteins). IPMK-mediated PIP3 production was also shown to be required for the full transcriptional activation of the nuclear hormone receptor, SF-1. (ii) The unique product of IPMK, Ins(1,4,5,6)P4, was revealed as a ligand required for activating class I HDAC-corepressor complexes. (iii) In a catalytic activity-independent manner, IPMK acts as a transcriptional coactivator for different transcription factors, including SRF, CBP, and p53. IPMK not only stabilizes the interaction between SRF and the SRF-binding DNA sequence, it also recruits transcriptional activating factors (e.g., acetyltransferases) into CREB-CBP- and p53-containing transcription complexes. The IPMK-dependent control of IEG expression was further validated in vivo using conditional IPMK-knockout mouse models. The selective loss of neuronal IPMK was shown to markedly decrease the DNA binding affinity of SRF and abrogate the ability of CBP to be appropriately recruited to CREB in response to neural stimulation. These molecular alterations appear to decrease the induction of IEGs, leading to behavioral defects in spatial memory. However, most of the other findings described in this review were established using in vitro or mammalian cell culture settings, and should thus be examined in vivo in the future. Recently, a germline deletion mutation in IPMK was discovered among familial and sporadic small intestinal carcinoid patients (Sei et al., 2015). This autosomal dominant mutation truncates the IPMK protein to a version that lacks the nuclear localization signal and the kinase domain, and thus the mutant protein shows nuclear localization defects and a lack of kinase activity. B lymphoblasts from carcinoid patients with mutant IPMK show misregulation of p53 activity in the nucleus, suggesting that intestinal carcinoid tumorigenesis could be promoted by insufficient p53-mediated control of genes related to apoptosis and cell-cycle arrest. Further comprehensive studies will be needed to fully elucidate how the other proposed nuclear functions of IPMK contribute to pathological dysregulation.