Posttranslational regulation of cyclin D1 by retinoic acid: A chemoprevention mechanism Journal Article

   


Authors: Langenfeld, J.; Kiyokawa, H.; Sekula, D.; Boyle, J.; Dmitrovsky, E.
Article Title: Posttranslational regulation of cyclin D1 by retinoic acid: A chemoprevention mechanism
Abstract: The retinoids are reported to reduce incidence of second primary aerodigestive cancers. Mechanisms for this chemoprevention are previously linked to all-trans retinoic acid (RA) signaling growth inhibition at G1 in carcinogen-exposed immortalized human bronchial epithelial cells. This study investigated how RA suppresses human bronchial epithelial cell growth at the G1-S cell cycle transition. RA signaled growth suppression of human bronchial epithelial cells and a decline in cyclin D1 protein but not mRNA expression. Exogenous cyclin D1 protein also declined after RA treatment of transfected, immortalized human bronchial epithelial cells, suggesting that posttranslational mechanisms were active in this regulation of cyclin D1 expression. Findings were extended by showing treatment with ubiquitin- dependent proteasome inhibitors: calpain inhibitor I and lactacystin each prevented this decreased cyclin D1 protein expression, despite RA treatment. Treatment with the cysteine proteinase inhibitor, E-64, did not prevent this cyclin D1 decline. High molecular weight cyclin D1 protein species appeared after proteasome inhibitor treatments, suggesting that ubiquitinated species were present. To learn whether RA directly promoted degradation of cyclin D1 protein, studies using human bronchial epithelial cell protein extracts and in vitro-translated cyclin D1 were performed. In vitro-translated cyclin D1 degraded more rapidly when incubated with extracts from RA treated vs. untreated cells. Notably, this RA-signaled cyclin D1 proteolysis depended on the C-terminal PEST sequence, a region rich in proline (P), glutamate (E), serine (S), and threonine (T). Taken together, these data highlight RA- induced cyclin D1 proteolysis as a mechanism signaling growth inhibition at G1 active in the prevention of human bronchial epithelial cell transformation.
Keywords: signal transduction; controlled study; human tissue; protein expression; unclassified drug; human cell; ubiquitin; protein analysis; cell cycle; chemoprophylaxis; proteasome endopeptidase complex; serine; protein degradation; cell line; cell transformation, neoplastic; gene expression regulation; cancer inhibition; protein processing, post-translational; cell transformation; epithelial cells; bronchus; threonine; bronchus mucosa; cyclin d1; multienzyme complexes; glutamic acid; molecular weight; retinoic acid; bronchi; normal human; proline; tretinoin; cysteine endopeptidases; lactacystin; calpastatin; humans; human; priority journal; article
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 94
Issue: 22
ISSN: 0027-8424
Publisher: National Academy of Sciences  
Date Published: 1997-10-28
Start Page: 12070
End Page: 12074
Language: English
DOI: 10.1073/pnas.94.22.12070
PUBMED: 9342364
PROVIDER: scopus
PMCID: PMC23705
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-0030691026&doi=10.1073%2fpnas.94.22.12070&partnerID=40&md5=94b34e3e0dba14f64a239843513e3b7c
Notes: Article -- Export Date: 17 March 2017 -- Source: Scopus
Altmetric
What is Altmetric?
Citation Impact
What is Dimensions Citation Badge?
BMJ Impact Analytics
MSK Authors
  1. Jay O Boyle
    148 Boyle
  2. Ethan Dmitrovsky
    98 Dmitrovsky
  3. David J Sekula
    5 Sekula
  4. Hiroaki Kiyokawa
    27 Kiyokawa
  5. John E. Langenfeld
    14 Langenfeld
Related MSK Work