The Degradation of Academic Dogma
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This regulation is driven by PK transcriptional repression of TP Moreover, since XBP1 transcriptional function is involved in a wide range of biological processes, one can speculate on the upstream influence of PK in these various XBP1-dependent phenotypes. Of note, the authors highlighted that most of PK targets were of mitochondrial origin suggesting an important role of nuclear PK in mitochondrial homeostasis.
This group also includes PK-regulated genes encoding protein, the degradation of which does not involve PK E3 ligase activity like monoamino oxidases A and B Jiang et al. Finally, this large group gathers potential PK targets identified by microarray. A RNAseq study of skin fibroblasts from either healthy or PD patients carrying PK mutations show a modulation of genes, which function and gene ontology indicate a link of PK with cell adhesion, cell growth, and amino acid and folate metabolism among others Gonzalez-Casacuberta et al.
Group 4 highlights the possible dual regulation of some genes and their translation products by both PK TF and E3 ligase activities, respectively. Thus, in this group, one can find p53, mitofusin 1, mitofusin 2, and voltage-dependent anion channel 1 VDAC that are validated E3 ligase substrates and potential PK TF targets Geisler et al. Given the enormous network of genes regulated by these TFs, one can envision a huge impact of PK in a variety of cellular functions.
It should be noted that TP53 is also a TF target of PK suggesting that both TF and ubiquitin ligase functions may be implicated in transcriptional and post-traductional control of a given target. Conversely, some of the above-cited proteins could well behave as PK E3 ligase substrates only, without being transcriptionally regulated by PK. It is clear that PK harbors ubiquitin ligase and TF functions, which could be both involved in gene regulation.
All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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PINK1-phosphorylated mitofusin 2 is a Parkin receptor for culling damaged mitochondria. Science , — Cho, S. SUMO1 promotes Abeta production via the modulation of autophagy. Autophagy 11, — Chu, D. Cloning and characterization of LUN, a novel ring finger protein that is highly expressed in lung and specifically binds to a palindromic sequence. Cookson, M. RING finger 1 mutations in Parkin produce altered localization of the protein. Cell Biol. De Strooper, B. Presenilins and gamma-secretase: structure, function, and role in Alzheimer Disease.
Cold Spring Harb. Duggan, S. Beyond gamma-secretase activity: the multifunctional nature of presenilins in cell signalling pathways. Duplan, E. ER-stress-associated functional link between Parkin and DJ-1 via a transcriptional cascade involving the tumor suppressor p53 and the spliced X-box binding protein XBP Cell Sci. Parkin differently regulates presenilin-1 and presenilin-2 functions by direct control of their promoter transcription. Duprez, E. PubMed Abstract Google Scholar.
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Fallon, L. Fang, S. Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p Finney, N.
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The cellular protein level of parkin is regulated by its ubiquitin like domain. Fulton, D. TFCat: the curated catalog of mouse and human transcription factors. Genome Biol. Geertz, M. Massively parallel measurements of molecular interaction kinetics on a microfluidic platform. Geisler, S.
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Glauser, L. Parkin promotes the ubiquitination and degradation of the mitochondrial fusion factor mitofusin 1. Goiran, T. Psychiatry 83, — Nuclear pmediated repression of autophagy involves PINK1 transcriptional down-regulation.
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Genome-wide mapping of in vivo protein-DNA interactions. Jolma, A. Methods for analysis of transcription factor dna-binding specificity in vitro. Sub Cell Biochem. Jung, Y. Loss of Parkin reduces inflammatory arthritis by inhibiting p53 degradation. Redox Biol. Kanno, M. Kao, S. DNA damage induces nuclear translocation of parkin.
The degradation of the academic dogma.
Kothinti, R. Kuroda, Y. Parkin enhances mitochondrial biogenesis in proliferating cells. Liu, J. Parkin targets HIF-1alpha for ubiquitination and degradation to inhibit breast tumor progression. Lovering, R. Identification and preliminary characterization of a protein motif related to the zinc finger. Lu, T. Gene regulation and DNA damage in the ageing human brain.