Hsp25 regulates the expression of p21(Waf1/Cip1/Sdi1) through multiple mechanisms.
Exposure of cells to external stresses leads to the induction or activation of certain proteins. Expression of heat shock proteins (Hsps) is induced in response to these stresses. Hsps are known to have molecular chaperone activities; but recent studies have shown that Hsps have a variety of functions such as the triggering of proliferation, differentiation, and apoptosis of cells. Previously, we found that overexpression of a 25 kDa Hsp (Hsp25) induced expression of cell cycle inhibitory protein p21 (Waf1/Cip1/Sdi1) in murine fibroblastoid L929 cells. However, the mechanisms underlying the induction of p21 by Hsp25 are unknown. In the present study, we investigated the mechanisms underlying the regulation of p21 expression by Hsp25 in these cells. The introduction of Hsp25 cDNA stimulated the accumulation of p21 transcripts through transcriptional but not posttranscriptional regulation in these cells. We also found that overexpression of Hsp25 markedly increased the translational rate of p21 and stabilized the protein. Studies involving proteasome inhibitors and Western blot analysis for ubiquitination of p21 demonstrated that the stabilization of p21 is regulated through a ubiquitin-independent pathway. However, no direct association of Hsp25 with p21 was observed. These findings suggest that Hsp25 induces p21 expression through multiple mechanisms, and that transcriptional, translational, and post-translational regulation are important in the regulation of p21.
Park
Sang-Hee
SH
The Research Center for Radiation Emergency Medicine, National Institute of Radiological Sciences, Anagawa, Inage-ku, Chiba 263-8555, Japan.
Lee
Yun-Sil
YS
Osawa
Yoshiaki
Y
Hachiya
Misao
M
Akashi
Makoto
M
D000818:Animals; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis* / Q000235:genetics; D018922:HL-60 Cells; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D006801:Humans; D051379:Mice; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D055551:HSP27 Heat-Shock Proteins; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; C486113:Hsbp1 protein, mouse; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D012333:RNA, Messenger