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| Status |
Public on May 01, 2018 |
| Title |
Acute HSF1 depletion induces cellular senescence through activation of the MDM2-p53-p21 pathway in human diploid fibroblasts |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Heat shock transcription factor 1 (HSF1) regulates the expression of a wide array of genes, controlling expression of heat shock proteins (HSPs) and cell growth. Although acute depletion of HSF1 induces cellular senescence, the underlying mechanisms are poorly understood. Here, we report that HSF1 depletion-induced senescence (HDIS) of human diploid fibroblasts (HDFs) was independent of HSP-mediated proteostasis, but dependent on activation of the p53-p21 pathway, partly because of increased expression of dehydrogenase/reductase 2 (DHRS2), a putative MDM2 inhibitor. We observed that HDIS occurred without decreased levels of major HSPs or increased proteotoxic stress in HDFs. Additionally, an inhibitor of HSP70 family proteins increased proteotoxicity and suppressed cell growth, but failed to induce senescence. Importantly, we found that activation of the p53-p21 pathway due to reduced MDM2-dependent p53 degradation was required for HDIS. Furthermore, we provide evidence that increased DHRS2 expression contribute to p53 stabilization and HDIS. Collectively, our observations uncovered a molecular pathway in which HSF1 depletion-induced DHRS2 expression leads to activation of the MDM2-p53-p21 pathway required for HDIS.
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| Overall design |
hTERT-immortalized human fibroblasts expressing doxycycline-inducible shRNA targeting HSF1 were treated with DOX for 0, 1, 3, 7 days and gene expression was measured.
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| Contributor(s) |
Oda T, Yamashita T |
| Citation(s) |
29632240 |
| Submission date |
Mar 02, 2018 |
| Last update date |
May 08, 2018 |
| Contact name |
Tsukasa Oda |
| E-mail(s) |
toda@gunma-u.ac.jp
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| Phone |
+81-27-220 8832
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| Organization name |
Gunma University
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| Department |
IMCR
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| Lab |
Laboratory of Molecular Genetics
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| Street address |
Showa-machi, 3-39-15
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| City |
Maebashi |
| State/province |
Gunma |
| ZIP/Postal code |
371-8512 |
| Country |
Japan |
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| Platforms (1) |
| GPL14550 |
Agilent-028004 SurePrint G3 Human GE 8x60K Microarray (Probe Name Version) |
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| Samples (4)
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| Relations |
| BioProject |
PRJNA436708 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE111355_RAW.tar |
12.6 Mb |
(http)(custom) |
TAR (of TXT) |
| Processed data included within Sample table |
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