title: Altered Ca(2+) signaling in cancer cells: proto-oncogenes and tumor suppressors targeting IP3 receptors.
abstract: Proto-oncogenes and tumor suppressors critically control cell-fate decisions like cell survival, adaptation and death. These processes are regulated by Ca(2+) signals arising from the endoplasmic reticulum, which at distinct sites is in close proximity to the mitochondria. These organelles are linked by different mechanisms, including Ca(2+)-transport mechanisms involving the inositol 1,4,5-trisphosphate receptor (IP3R) and the voltage-dependent anion channel (VDAC). The amount of Ca(2+) transfer from the endoplasmic reticulum to mitochondria determines the susceptibility of cells to apoptotic stimuli. Suppressing the transfer of Ca(2+) from the endoplasmic reticulum to the mitochondria increases the apoptotic resistance of cells and may decrease the cellular responsiveness to apoptotic signaling in response to cellular damage or alterations. This can result in the survival, growth and proliferation of cells with oncogenic features. Clearly, proper maintenance of endoplasmic reticulum Ca(2+) homeostasis and dynamics including its links with the mitochondrial network is essential to detect and eliminate altered cells with oncogenic features through the apoptotic pathway. Proto-oncogenes and tumor suppressors exploit the central role of Ca(2+) signaling by targeting the IP3R. There are an increasing number of reports showing that activation of proto-oncogenes or inactivation of tumor suppressors directly affects IP3R function and endoplasmic reticulum Ca(2+) homeostasis, thereby decreasing mitochondrial Ca(2+) uptake and mitochondrial outer membrane permeabilization. In this review, we provide an overview of the current knowledge on the proto-oncogenes and tumor suppressors identified as IP3R-regulatory proteins and how they affect endoplasmic reticulum Ca(2+) homeostasis and dynamics.
authors.affiliation: Department Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium.
authors.forename: Haidar
authors.initials: H
authors.lastname: Akl
authors.forename: Geert
authors.initials: G
authors.lastname: Bultynck
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D000071186:Beclin-1; D020013:Calcium Signaling / Q000502:physiology*; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000502:physiology*; D008565:Membrane Proteins / Q000502:physiology; D008840:Microfilament Proteins / Q000502:physiology; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009369:Neoplasms / Q000378:metabolism*; D009687:Nuclear Proteins / Q000502:physiology; D000071156:Promyelocytic Leukemia Protein; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D011519:Proto-Oncogenes; D014157:Transcription Factors / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D051020:bcl-X Protein / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C482653:ITPRID2 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008565:Membrane Proteins; D008840:Microfilament Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D051020:bcl-X Protein; C070576:PML protein, human; D051057:Proto-Oncogene Proteins c-akt