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Regulation of E2F1 activity via PKA-mediated phosphorylations.

Authors
  • Ertosun, Mustafa Gökhan1
  • DİlmaÇ, Sayra2
  • Hapİl, Fatma Zehra3
  • TanriÖver, Gamze2
  • KÖksoy, Sadi4
  • ÖzeŞ, Osman Nidai5
  • 1 Department of Plastic, Reconstructive, and Aesthetic Surgery, Faculty of Medicine, Akdeniz University, Antalya Turkey. , (Turkey)
  • 2 Department of Histology and Embriology, Faculty of Medicine, Akdeniz University, Antalya Turkey. , (Turkey)
  • 3 Department of Medical Biology and Genetics, Faculty of Medicine, Akdeniz University, Antalya Turkey. , (Turkey)
  • 4 Department of Medical Microbiology, Faculty of Medicine, Akdeniz University, Antalya Turkey. , (Turkey)
  • 5 Altay Therapeutics, San Bruno, CA USA.
Type
Published Article
Journal
Turkish journal of biology = Turk biyoloji dergisi
Publication Date
Jan 01, 2020
Volume
44
Issue
5
Pages
215–229
Identifiers
DOI: 10.3906/biy-2003-9
PMID: 33110360
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

E2F1 becomes activated during the G1 phase of the cell cycle, and posttranslational modifications modulate its activity. Activation of G-protein coupled receptors (GPCR) by many ligands induces the activation of adenylate cyclases and the production of cAMP, which activates the PKA enzyme. Activated PKA elicits its biological effect by phosphorylating the target proteins containing serine or threonine amino acids in the RxxS/T motif. Since PKA activation negatively regulates cell proliferation, we thought that activated PKA would negatively affect the activity of E2F1. In line with this, when we analyzed the amino acid sequence of E2F1, we found 3 hypothetical consensus PKA phosphorylation sites located at 127-130, 232-235, and 361-364 positions and RYET, RLLS, and RMGS sequences. After showing the binding and phosphorylation of E2F1 by PKA, we converted the codons of Threonine-130, Serine-235, and Serine-364 to Alanine and Glutamic acid codons on the eukaryotic E2F1 expression vector we had previously created. We confirmed the phosphorylation of T130, S235, and S364 by developing monoclonal antibodies against phospho-specific forms of these sites and showed that their phosphorylation is cell cycle-dependent. According to our results, PKA-mediated phosphorylation of E2F1 by PKA inhibits proliferation and glucose uptake and induces caspase-3 activation and senescence. Copyright © 2020 The Author(s).

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