Identification and characterization of murine mHAUSP encoding a deubiquitinating enzyme that regulates the status of p53 ubiquitination

Lim, Soo-Kyung; Shin, Jumi A.; Kim, Yong Soo; Baek, Kwang‐Hyun

doi:10.3892/ijo.24.2.357

Cited by 16 publications

(32 citation statements)

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“…Deubiquitinating enzymes remove ubiquitins from ubiquitin-conjugated protein substrates. HAUSP, one of the deubiquitinating enzymes, separates ubiquitins from polyubiquitinated p53 and stabilizes p53 Lim et al, 2004). It has been demonstrated that the overexpression of HAUSP regulates p53-dependent apoptosis and inhibition of cell growth .…”

Section: Discussionmentioning

confidence: 99%

“…A deubiquitinating enzyme assay, based on the cleavage of ubiquitin-β-galactosidase fusion proteins, has been described previously (Lim et al, 2004). The wild-type mHAUSP cDNA and cDNA containing a missense mutant form, mHAUSP (C224S), mHAUSP (Q231E), mHAUSP (D296A), mHAUSP (H457Q), mHAUSP (H465Q), and mHAUSP (D482A) were used.…”

Section: Deubiquitinating Enzyme Assay In Vitromentioning

confidence: 99%

“…It has been previously demonstrated that the conserved Cys at amino acid 224 is required for the deubiquitinating activity of mHAUSP (Lim et al, 2004). We have generated mutations at conserved amino acid residues throughout the polypeptide sequence, which were Q231E (glutamine to glutamic acid at amino acid 231), D296A (aspartic acid to alanine at amino acid 296), H457Q (histidine to glutamine at amino acid 457), H465Q (histidine to glutamine at amino acid 465), and D482A (aspartic acid to alanine at amino acid 482) ( Fig.…”

Section: Essential Amino Acids For In Vitro Deubiquitinating Activitymentioning

confidence: 99%

“…They are different in length and functional domains, but contain highly conserved Cys, His, and Asp residues (Wilkinson, 2000;Baek et al, 2004;Lim et al, 2004).…”

mentioning

confidence: 99%

“…This feedback-mediated p53 stabilization is Mdm2 dependent (Cummins et al, 2004;Li et al, 2004). HAUSP belongs to the ubiquitin-specific processing protease (UBP) family of deubiquitinating enzyme and contains the characteristic Cys, Asp, and His motifs at the core enzymatic domain and localizes with the promyelocytic leukemia (PML) nuclear body (Everett et al, 1997;Lim et al, 2004).…”

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confidence: 99%

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Structural characterization of mouse HAUSP, a proteolysis regulator of p53

Lee

Yoo

Baek

2004

Korean Journal of Biological Sciences

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Section: Discussionmentioning

confidence: 99%

Section: Deubiquitinating Enzyme Assay In Vitromentioning

confidence: 99%

Section: Essential Amino Acids For In Vitro Deubiquitinating Activitymentioning

confidence: 99%

“…They are different in length and functional domains, but contain highly conserved Cys, His, and Asp residues (Wilkinson, 2000;Baek et al, 2004;Lim et al, 2004).…”

mentioning

confidence: 99%

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confidence: 99%

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Structural characterization of mouse HAUSP, a proteolysis regulator of p53

Lee

Yoo

Baek

2004

Korean Journal of Biological Sciences

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HAUSP, a deubiquitinating enzyme for p53, is polyubiquitinated, polyneddylated, and dimerized

Lee

Kim

et al. 2005

FEBS Letters

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The tumor suppressor protein p53 is ubiquitinated and neddylated by MDM2 and then degraded by 26S proteasome. However, p53 is stabilized by the HAUSP (Herpes-virus-associated ubiquitin-specific protease) deubiquitinating enzyme. In this study, we discovered that rat HAUSP (rHAUSP) is polyubiquitinated, polyneddylated, and dimerized using co-immunoprecipitation assays. This suggests that rHAUSP may function as a dimer or multimer and is also degraded through the proteasome-mediated degradation. Transfection of rHAUSP into RGC-Lac-Z cell line with the integrated p53 response element revealed that rHAUSP contributed to p53 stabilization, and a rHAUSP (C224S) mutant contributed to p53 destabilization in a dose-dependent manner.

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A Dynamic Role of HAUSP in the p53-Mdm2 Pathway

Li¹,

Brooks²,

et al. 2004

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Our previous study showed that ubiquitination of p53 is reversible and that the ubiquitin hydrolase HAUSP can stabilize p53 by deubiquitination. Here, we found that partial reduction of endogenous HAUSP levels by RNAi indeed destabilizes endogenous p53; surprisingly, however, nearly complete ablation of HAUSP stabilizes and activates p53. We further show that this phenomenon occurs because HAUSP stabilizes Mdm2 in a p53-independent manner, providing an interesting feedback loop in p53 regulation. Notably, HAUSP is required for Mdm2 stability in normal cells; in HAUSP-ablated cells, self-ubiquitinated-Mdm2 becomes extremely unstable, leading to indirect p53 activation. Furthermore, this feedback regulation is specific to Mdm2; in HeLa cells, where p53 is preferentially degraded by viral E6-dependent ubiquitination, depletion of HAUSP fails to activate p53. This study provides an example of an ubiquitin ligase (Mdm2) that is directly regulated by a deubiquitinase (HAUSP) and also reveals a dynamic role of HAUSP in the p53-Mdm2 pathway.

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Identification and characterization of murine mHAUSP encoding a deubiquitinating enzyme that regulates the status of p53 ubiquitination

Cited by 16 publications

References 0 publications

Structural characterization of mouse HAUSP, a proteolysis regulator of p53

Structural characterization of mouse HAUSP, a proteolysis regulator of p53

HAUSP, a deubiquitinating enzyme for p53, is polyubiquitinated, polyneddylated, and dimerized

A Dynamic Role of HAUSP in the p53-Mdm2 Pathway

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