Crucial role of TSC-22 in preventing the proteasomal degradation of p53 in cervical cancer

Cheol Hee Yoon, Seung Bae Rho, Seong Tae Kim, Seongho Kho, Junsoo Park, Ik Soon Jang, Seonock Woo, Sung Soon Kim, Je Ho Lee, Seung Hoon Lee

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

The p53 tumor suppressor function can be compromised in many tumors by the cellular antagonist HDM2 and human papillomavirus oncogene E6 that induce p53 degradation. Restoration of p53 activity has strong therapeutic potential. Here, we identified TSC-22 as a novel p53-interacting protein and show its novel function as a positive regulator of p53. We found that TSC-22 level was significantly down-regulated in cervical cancer tissues. Moreover, over-expression of TSC-22 was sufficient to inhibit cell proliferation, promote cellular apoptosis in cervical cancer cells and suppress growth of xenograft tumors in mice. Expression of also TSC-22 enhanced the protein level of p53 by protecting it from poly-ubiquitination. When bound to the motif between amino acids 100 and 200 of p53, TSC-22 inhibited the HDM2- and E6-mediated p53 poly-ubiquitination and degradation. Consequently, ectopic over-expression of TSC-22 activated the function of p53, followed by increased expression of p21Waf1/Cip1 and PUMA in human cervical cancer cell lines. Interestingly, TSC-22 did not affect the interaction between p53 and HDM2. Knock-down of TSC-22 by small interfering RNA clearly enhanced the poly-ubiquitination of p53, leading to the degradation of p53. These results suggest that TSC-22 acts as a tumor suppressor by safeguarding p53 from poly-ubiquitination mediated-degradation.

Original languageEnglish
Article numbere42006
JournalPloS one
Volume7
Issue number8
DOIs
Publication statusPublished - 2012 Aug 1

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uterine cervical neoplasms
Ubiquitination
Uterine Cervical Neoplasms
Tumors
Degradation
neoplasms
degradation
Neoplasms
Cells
Amino Acid Motifs
Papillomaviridae
oncogenes
Cell proliferation
small interfering RNA
Oncogenes
Heterografts
Small Interfering RNA
Restoration
antagonists
cell proliferation

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Yoon, C. H., Rho, S. B., Kim, S. T., Kho, S., Park, J., Jang, I. S., ... Lee, S. H. (2012). Crucial role of TSC-22 in preventing the proteasomal degradation of p53 in cervical cancer. PloS one, 7(8), [e42006]. https://doi.org/10.1371/journal.pone.0042006
Yoon, Cheol Hee ; Rho, Seung Bae ; Kim, Seong Tae ; Kho, Seongho ; Park, Junsoo ; Jang, Ik Soon ; Woo, Seonock ; Kim, Sung Soon ; Lee, Je Ho ; Lee, Seung Hoon. / Crucial role of TSC-22 in preventing the proteasomal degradation of p53 in cervical cancer. In: PloS one. 2012 ; Vol. 7, No. 8.
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Yoon, CH, Rho, SB, Kim, ST, Kho, S, Park, J, Jang, IS, Woo, S, Kim, SS, Lee, JH & Lee, SH 2012, 'Crucial role of TSC-22 in preventing the proteasomal degradation of p53 in cervical cancer', PloS one, vol. 7, no. 8, e42006. https://doi.org/10.1371/journal.pone.0042006

Crucial role of TSC-22 in preventing the proteasomal degradation of p53 in cervical cancer. / Yoon, Cheol Hee; Rho, Seung Bae; Kim, Seong Tae; Kho, Seongho; Park, Junsoo; Jang, Ik Soon; Woo, Seonock; Kim, Sung Soon; Lee, Je Ho; Lee, Seung Hoon.

In: PloS one, Vol. 7, No. 8, e42006, 01.08.2012.

Research output: Contribution to journalArticle

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T1 - Crucial role of TSC-22 in preventing the proteasomal degradation of p53 in cervical cancer

AU - Yoon, Cheol Hee

AU - Rho, Seung Bae

AU - Kim, Seong Tae

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AU - Park, Junsoo

AU - Jang, Ik Soon

AU - Woo, Seonock

AU - Kim, Sung Soon

AU - Lee, Je Ho

AU - Lee, Seung Hoon

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N2 - The p53 tumor suppressor function can be compromised in many tumors by the cellular antagonist HDM2 and human papillomavirus oncogene E6 that induce p53 degradation. Restoration of p53 activity has strong therapeutic potential. Here, we identified TSC-22 as a novel p53-interacting protein and show its novel function as a positive regulator of p53. We found that TSC-22 level was significantly down-regulated in cervical cancer tissues. Moreover, over-expression of TSC-22 was sufficient to inhibit cell proliferation, promote cellular apoptosis in cervical cancer cells and suppress growth of xenograft tumors in mice. Expression of also TSC-22 enhanced the protein level of p53 by protecting it from poly-ubiquitination. When bound to the motif between amino acids 100 and 200 of p53, TSC-22 inhibited the HDM2- and E6-mediated p53 poly-ubiquitination and degradation. Consequently, ectopic over-expression of TSC-22 activated the function of p53, followed by increased expression of p21Waf1/Cip1 and PUMA in human cervical cancer cell lines. Interestingly, TSC-22 did not affect the interaction between p53 and HDM2. Knock-down of TSC-22 by small interfering RNA clearly enhanced the poly-ubiquitination of p53, leading to the degradation of p53. These results suggest that TSC-22 acts as a tumor suppressor by safeguarding p53 from poly-ubiquitination mediated-degradation.

AB - The p53 tumor suppressor function can be compromised in many tumors by the cellular antagonist HDM2 and human papillomavirus oncogene E6 that induce p53 degradation. Restoration of p53 activity has strong therapeutic potential. Here, we identified TSC-22 as a novel p53-interacting protein and show its novel function as a positive regulator of p53. We found that TSC-22 level was significantly down-regulated in cervical cancer tissues. Moreover, over-expression of TSC-22 was sufficient to inhibit cell proliferation, promote cellular apoptosis in cervical cancer cells and suppress growth of xenograft tumors in mice. Expression of also TSC-22 enhanced the protein level of p53 by protecting it from poly-ubiquitination. When bound to the motif between amino acids 100 and 200 of p53, TSC-22 inhibited the HDM2- and E6-mediated p53 poly-ubiquitination and degradation. Consequently, ectopic over-expression of TSC-22 activated the function of p53, followed by increased expression of p21Waf1/Cip1 and PUMA in human cervical cancer cell lines. Interestingly, TSC-22 did not affect the interaction between p53 and HDM2. Knock-down of TSC-22 by small interfering RNA clearly enhanced the poly-ubiquitination of p53, leading to the degradation of p53. These results suggest that TSC-22 acts as a tumor suppressor by safeguarding p53 from poly-ubiquitination mediated-degradation.

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