title: Adhesion to fibronectin induces p27(Kip1) nuclear accumulation through down-regulation of Jab1 and contributes to cell adhesion-mediated drug resistance (CAM-DR) in RPMI 8,226 cells.
abstract: Mounting evidence has been shown that integrin-mediated cellular adhesion confers resistance to chemotherapy of multiple myeloma. The molecular mechanism underlying cell adhesion-mediated drug resistance (CAM-DR) is, however, poorly understood. In this report, we demonstrated that RPMI 8,226 cells accumulated p27(Kip1) in the nucleus when they were adhered to fibronectin (FN). The adhesion-mediated p27(Kip1) nuclear recruitment was regulated via the down-regulation of Jab1, a negative regulator of cell cycle. Overexpression of Jab1 reversed the elevated p27(Kip1) in the nucleus, which needed phosphorylation of p27(Kip1) on Serine 10, whereas inhibition of Jab1 by siRNA further increased the elevated p27(Kip1). Furthermore, we found overexpression of Jab1 did not affect 8,226 cells adhesion to FN, but reversed doxorubicin or mitoxantrone-induced CAM-DR phenotype. In conclusion, our data suggest that Jab1 plays an important role in CAM-DR, which depends on pSer10-p27(Kip1)-mediated subcellular localization of p27(Kip1). The understanding of this novel molecular mechanism may prove valuable in designing new therapeutic approaches for CAM-DR in Multiple myeloma.
authors.affiliation: Jiangsu Institute of Hematology, The First Affiliated Hospital, Soochow University, Suzhou, Jiangsu, China.
authors.forename: Min
authors.initials: M
authors.lastname: Fei
authors.forename: Qinglei
authors.initials: Q
authors.lastname: Hang
authors.forename: Sicong
authors.initials: S
authors.lastname: Hou
authors.forename: Songbin
authors.initials: S
authors.lastname: He
authors.forename: Changgeng
authors.initials: C
authors.lastname: Ruan
mesh_terms: D000075686:COP9 Signalosome Complex; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism*; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D005353:Fibronectins / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008856:Microscopy, Fluorescence; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D010447:Peptide Hydrolases / Q000378:metabolism*; D010766:Phosphorylation
chemical_list: C436291:CDKN1B protein, human; D005353:Fibronectins; D047908:Intracellular Signaling Peptides and Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex