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A network of substrates of the E3 ubiquitin ligases MDM2 and HUWE1 control apoptosis independently of p53.

Publication ,  Journal Article
Kurokawa, M; Kim, J; Geradts, J; Matsuura, K; Liu, L; Ran, X; Xia, W; Ribar, TJ; Henao, R; Dewhirst, MW; Kim, W-J; Lucas, JE; Wang, S ...
Published in: Sci Signal
May 7, 2013

In the intrinsic pathway of apoptosis, cell-damaging signals promote the release of cytochrome c from mitochondria, triggering activation of the Apaf-1 and caspase-9 apoptosome. The ubiquitin E3 ligase MDM2 decreases the stability of the proapoptotic factor p53. We show that it also coordinated apoptotic events in a p53-independent manner by ubiquitylating the apoptosome activator CAS and the ubiquitin E3 ligase HUWE1. HUWE1 ubiquitylates the antiapoptotic factor Mcl-1, and we found that HUWE1 also ubiquitylated PP5 (protein phosphatase 5), which indirectly inhibited apoptosome activation. Breast cancers that are positive for the tyrosine receptor kinase HER2 (human epidermal growth factor receptor 2) tend to be highly aggressive. In HER2-positive breast cancer cells treated with the HER2 tyrosine kinase inhibitor lapatinib, MDM2 was degraded and HUWE1 was stabilized. In contrast, in breast cancer cells that acquired resistance to lapatinib, the abundance of MDM2 was not decreased and HUWE1 was degraded, which inhibited apoptosis, regardless of p53 status. MDM2 inhibition overcame lapatinib resistance in cells with either wild-type or mutant p53 and in xenograft models. These findings demonstrate broader, p53-independent roles for MDM2 and HUWE1 in apoptosis and specifically suggest the potential for therapy directed against MDM2 to overcome lapatinib resistance.

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Published In

Sci Signal

DOI

EISSN

1937-9145

Publication Date

May 7, 2013

Volume

6

Issue

274

Start / End Page

ra32

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Ubiquitin-Protein Ligases
  • Tumor Suppressor Proteins
  • Tumor Suppressor Protein p53
  • Substrate Specificity
  • Signal Transduction
  • Receptor, erbB-2
  • Receptor, ErbB-2
  • RNA Interference
  • Quinazolines
 

Citation

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Kurokawa, M., Kim, J., Geradts, J., Matsuura, K., Liu, L., Ran, X., … Kornbluth, S. (2013). A network of substrates of the E3 ubiquitin ligases MDM2 and HUWE1 control apoptosis independently of p53. Sci Signal, 6(274), ra32. https://doi.org/10.1126/scisignal.2003741
Kurokawa, Manabu, Jiyeon Kim, Joseph Geradts, Kenkyo Matsuura, Liu Liu, Xu Ran, Wenle Xia, et al. “A network of substrates of the E3 ubiquitin ligases MDM2 and HUWE1 control apoptosis independently of p53.Sci Signal 6, no. 274 (May 7, 2013): ra32. https://doi.org/10.1126/scisignal.2003741.
Kurokawa M, Kim J, Geradts J, Matsuura K, Liu L, Ran X, et al. A network of substrates of the E3 ubiquitin ligases MDM2 and HUWE1 control apoptosis independently of p53. Sci Signal. 2013 May 7;6(274):ra32.
Kurokawa, Manabu, et al. “A network of substrates of the E3 ubiquitin ligases MDM2 and HUWE1 control apoptosis independently of p53.Sci Signal, vol. 6, no. 274, May 2013, p. ra32. Pubmed, doi:10.1126/scisignal.2003741.
Kurokawa M, Kim J, Geradts J, Matsuura K, Liu L, Ran X, Xia W, Ribar TJ, Henao R, Dewhirst MW, Kim W-J, Lucas JE, Wang S, Spector NL, Kornbluth S. A network of substrates of the E3 ubiquitin ligases MDM2 and HUWE1 control apoptosis independently of p53. Sci Signal. 2013 May 7;6(274):ra32.

Published In

Sci Signal

DOI

EISSN

1937-9145

Publication Date

May 7, 2013

Volume

6

Issue

274

Start / End Page

ra32

Location

United States

Related Subject Headings

  • Xenograft Model Antitumor Assays
  • Ubiquitin-Protein Ligases
  • Tumor Suppressor Proteins
  • Tumor Suppressor Protein p53
  • Substrate Specificity
  • Signal Transduction
  • Receptor, erbB-2
  • Receptor, ErbB-2
  • RNA Interference
  • Quinazolines