Retinoic acid induces p27Kip1 nuclear accumulation by modulating its phosphorylation

Cancer Research
A BorrielloFulvio Della Ragione

Abstract

All-trans-retinoic acid (ATRA), the most biologically active metabolite of vitamin A, controls cell proliferation, apoptosis, and differentiation depending on the cellular context. These activities point to ATRA as a candidate for cancer therapy. A pivotal effect of the molecule is the modulation of p27Kip1, a cyclin-dependent kinase (CDK) inhibitor (CDKI). Here, we investigate the mechanisms by which ATRA regulates p27Kip1 level in LAN-5, a neuroblastoma cell line. When added to the cells, ATRA causes a rapid nuclear increase of p27Kip1, which clearly precedes growth arrest. The early buildup is not due to impairment of the CDKI degradation, in contrast to previous observations. Particularly, we did not detect the down-regulation of Skp2 and Cks1, two proteins involved in the nuclear ubiquitin-dependent p27Kip1 removal. Moreover, the morphogen does not impair the CDKI nuclear export and does not cause CDK2 relocalization. The characterization of CDKI isoforms by two-dimensional PAGE/immunoblotting showed that ATRA induces an early nuclear up-regulation of monophosphorylated p27Kip1. Immunologic studies established that this isoform corresponds to p27Kip1 phosphorylated on S10. The buildup of phospho(S10)p27Kip1 precedes the CD...Continue Reading

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Citations

Oct 19, 2010·Carcinogenesis·Adriana BorrielloFulvio Della Ragione
Mar 2, 2011·Expert Opinion on Therapeutic Targets·Adriana BorrielloFulvio Della Ragione
Jul 29, 2009·Trends in Neurosciences·Verne S CavinessPradeep G Bhide
Jul 11, 2008·Journal of Cellular Physiology·Maria RaduKenneth J Soprano
Aug 6, 2013·American Journal of Hematology·Gian Luca ForniFulvio Della Ragione
Dec 19, 2015·Oxidative Medicine and Cellular Longevity·Adriana BorrielloFulvio Della Ragione
Jul 20, 2007·Differentiation; Research in Biological Diversity·Nigel P Mongan, Lorraine J Gudas
Jan 7, 2015·The International Journal of Biochemistry & Cell Biology·Ilaria CaldarelliAdriana Borriello
Sep 17, 2020·Biomolecules·Gian Luigi RussoAdriana Borriello
Apr 14, 2007·Molecular Cancer Therapeutics·Maxy De los SantosAna Aranda
Feb 7, 2021·Science Advances·Vidyasagar KoduriWilliam G Kaelin

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