Premium
Depletion of CRBN leads to proliferative cellular senescence by altering the level of cell cycle proteins
Author(s) -
Jeon Seungje,
Yoon Yiseul,
Yang Seungjoo,
Park ChulSeung
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.533.109
Subject(s) - cereblon , cell cycle , microbiology and biotechnology , cyclin dependent kinase , cell growth , biology , senescence , cell , genetics , ubiquitin , ubiquitin ligase , gene
Cereblon (CRBN) is the direct target of the immunomodulatory drugs (IMiD), such as lenalidomide, and the treatment of IMiDs is known to inhibit the proliferative activities of cancerous cells such as multiple myeloma. The expression level of CRBN protein is varied in different cancer cells and many somatic mutations in CRBN gene are found in numerous cancer patients. The mouse embryonic fibroblast (MEF) lacking Crbn was previously shown to be resistant to various cellular stresses (K.M. Lee et al. / Biochemical and Biophysical Research Communications 458 (2015) 34–39). However, the role of CRBN in cell proliferation and its regulation is still poorly understood. We observed that the Crbn‐knockout (KO) MEFs showed accelerated cell proliferation, and the increased level of replicative and premature senescence. We thus evaluated the level of cell cycle proteins such as cyclins, cyclin‐dependent kinases (CDK), and CDK inhibitors. We found that the expression of several cell cycle proteins was specifically altered by depletion of CRBN protein. In addition, the flow cytometric analyses showed the increased level of cell arrest at G2/M phase for CRBN KO cells by. Furthermore, the lifespan of Crbn KO mice was found to decrease compared to that of WT mice. Thus, CRBN deficiency may induce proliferative senescence via modulating the level of cell cycle proteins such as cyclins and CDK inhibitors. We are currently investigating the underlying mechanism for the specific alteration of cell cycle proteins induced by CRBN depletion. Support or Funding Information This work was supported by GIST Research Institute(GRI) grant funded by the GIST in 2017. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .