Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033774 (pruritus)
 14,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Itch is a member of the HECT family of ubiquitin E3 ligases, and regulates the stability of several proteins involved in response to genotoxic stress. We have previously shown that p73 and p63, two members of the p53 family of tumour suppressors, are targets for Itch-mediated ubiquitylation and degradation. Here, we show that depletion of Itch by RNA interference augments apoptosis upon treatment with chemotherapeutic drugs. We also show that cells with no functional p53 are more sensitive to Itch depletion, highlighting the importance that changes in levels of Itch may play in majority of cancers, where p53 is absent or mutated. Furthermore, reintroduction of Itch in fibroblasts obtained from Itch deficient mice results in reduced cell death upon DNA damage. Overall our findings suggest that inhibition of Itch potentiates the effect of chemotherapeutic drugs revealing the pharmacological potentials of targeting Itch for cancer therapy.
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PMID:Itch inhibition regulates chemosensitivity in vitro. 1764 Jun 19

UV radiation is a major environmental carcinogen. The oncoprotein c-Jun that is required for development of skin cancer is stabilized by UV radiation. The mechanism leading to its stabilization after exposure to UV is not known. The lack of knowledge was particularly sharpened, after the discovery that JNK, the most potent positive regulator of c-Jun, activates Itch, an E3-ligase of c-Jun and JunB. In this study we demonstrate that the expression of all three E3 ubiquitin ligases of c-Jun is down-regulated by UV. The levels of Itch/AIP4 and Fbw7alpha transcripts are reduced following UV exposure in every cell line examined. Repression of hCOP1 and its associated protein hDET1, which is required for c-Jun degradation, is cell type dependent. Expression of Fbw7alpha is down-regulated by UVC or UVB, independently of the p53, MAPK and the PKC pathways but the repression is inhibited in the absence of active Fbw7 proteins suggesting that a target protein of Fbw7 is involved in Fbw7 expression/repression. The repression does not require protein synthesis and UV does not change Fbw7 mRNA stability. The characteristics of Fbw7alpha repression perfectly match with those of c-Jun induction. Unlike UV, ionizing radiation does not repress Fbw7alpha and does not induce c-Jun. In addition, the repression kinetics correlates tightly with the kinetics of c-Jun induction by UV. Moreover, abrogation of Fbw7 UV-responsiveness abolishes c-Jun induction by UV, and knockdown of Fbw7 results in elevated basal expression of c-Jun but reduced UV-dependent induction thus, proving the essential role of this repression in c-Jun induction by UV.
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PMID:Transcriptional repression of c-Jun's E3 ubiquitin ligases contributes to c-Jun induction by UV. 1829 47

Understanding the mechanism of cisplatin (CDDP) action may improve therapeutic strategy for ovarian cancer. Although p53 and FLICE-like inhibitory protein (FLIP) are determinants of CDDP sensitivity in ovarian cancer, the interaction between p53 and FLIP remains poorly understood. Here, using two chemosensitive ovarian cancer cell lines and various molecular and cellular approaches, we show that CDDP induces p53-dependent FLIP ubiquitination and degradation, and apoptosis in vitro. Moreover, we showed that Itch (an E3 ligase) forms a complex with FLIP and p53 upon CDDP treatment. These results suggest that p53 facilitates FLIP down-regulation by CDDP-induced FLIP ubiquitination and proteasomal degradation.
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PMID:Cisplatin induces p53-dependent FLICE-like inhibitory protein ubiquitination in ovarian cancer cells. 1855 94

The members of the tumor suppressor p53 family are under tight regulation by distinct ubiquitin-protein isopeptide (E3) ligases. The level of p73 is regulated by the E3 ligase Itch. Itch levels are sharply reduced in response to DNA damage with concomitant p73 accumulation and activation. The mechanism of controlling Itch level is not known. We show that the Itch promoter is a target of the transcription activator Runx. Yes-associated protein (Yap1) is a shared transcription co-activator of Runx and p73. Under normal conditions, the Runx-Yap1 complex binds the Itch promoter and supports its transcription and p73 degradation. In response to DNA damage, Yap1 is phosphorylated by c-Abl at the position Tyr-357. The modified Yap1 does not co-activate Runx in supporting Itch transcription. The subsequent reduction in the Itch level gives rise to p73 accumulation. These results demonstrate how Yap1 supports degradation of p73 via Runx and how it plays an opposite role in response to DNA damage.
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PMID:A regulatory circuit controlling Itch-mediated p73 degradation by Runx. 1870 49

Netrins and their receptors deleted in colon cancer (DCC), neogenin, UNC5, and integrins are involved in axon guidance, epithelial morphogenesis, vascular pattering, cancer cell survival, invasion, tumor angiogenesis, and metastasis. Here, we considered the possible contribution of the p53-related apoptosis mediators p63 and p73 in the mechanisms underlying the antagonism between netrin-1 and DCC at the cell death control. We have showed that ectopic expression and external addition of netrin-1 in HeLa and HEK-293 cells with inactive p53 lead to impaired cell viability and induction of apoptosis. These responses were associated with up-regulation of the proapoptotic protein TAp73alpha, decreased Bcl-2/Bax ratio, and caspase-3 cleavage, with no change in protein levels of the antiapoptotic NH(2)-terminal-truncated DeltaNp73alpha isoform, p73 adapter Yap-1 and p73 E3 ubiquitin ligase Itch, and p63, as well as the transcripts encoding p63, TAp73alpha, and DeltaNp73alpha. However, the proteasome inhibitor MG132 potentiated, while DCC counteracted, netrin-1-induced TAp73alpha. Consistently, netrin-1 expression correlated with stabilization of the TAp73alpha protein and lower levels of TAp73alpha ubiquitination that was conversely enhanced by DCC, in a netrin-dependent manner. Our data indicate that netrin-1 selectively up-regulates TAp73alpha by preventing its ubiquitination and degradation. Targeted repression of p73alpha by shRNA reversed TAp73alpha and the apoptosis induced by netrin-1, and exacerbated the growth of HeLa tumor xenografts. Apoptosis induced by cisplatin was markedly enhanced in netrin-1 or DCC-expressing cells. Collectively, our data reveal that the transcriptionally active TAp73alpha tumor suppressor is implicated in the apoptosis induced by netrin-1 in a p53-independent and DCC/ubiquitin-proteasome dependent manner.
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PMID:Netrin-1 induces apoptosis in human cervical tumor cells via the TAp73alpha tumor suppressor. 1892 94

Chronic lymphocytic leukemia (CLL) is characterized by cells that exhibit dysfunctional apoptosis. Here, we show that deacetylase inhibition led to the E2F1- and myc-mediated transcriptional activation of the microRNA miR106b in primary CLL cells. Induction of miR106b was associated with a down-regulation in the levels of the E3-ubiquitin ligase Itch. Decreases in Itch protein levels were associated with a reciprocal accumulation of its proapoptotic substrate, TAp73 (p73), and induction of p53 up-regulated modulator of apoptosis (PUMA) mRNA and protein. This event was accompanied by mitochondrial dysfunction, processing of caspase-9, and apoptosis of CLL cells. Ectopic expression of miR106b in CLL cells demonstrated that Itch was a direct target of miR106b such that miR106b-induced decreases in Itch resulted in an accumulation of p73. Thus, our results identify a novel regulatory mechanism wherein microRNA regulate cell survival by mediating the posttranscriptional down-regulation of an ubiquitin ligase, leading to the induction of a proapoptotic regulator in malignant cells. Silencing of miRNA expression in CLL may selectively suppress proapoptotic pathways, providing such tumors with a survival advantage. Consequently, chemotherapeutic drugs that activate miR106b could initiate a p53-independent mechanism that targets CLL cells.
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PMID:Specific activation of microRNA106b enables the p73 apoptotic response in chronic lymphocytic leukemia by targeting the ubiquitin ligase Itch for degradation. 1954 40

Although Akt is a determinant of cisplatin (cis-diaminedichloroplatinum (CDDP)) resistance in ovarian cancer cells, which is related in part to its inhibitory action on p53 activation, precisely how Akt confers CDDP resistance is unclear. In this study, we show that CDDP induced p53-dependent Fas-associated death domain-like interleukin-1beta-converting enzyme (FLICE)-like inhibitory protein (FLIP) degradation in chemosensitive ovarian cancer cells but not their resistant counterparts. CDDP induced FLIP-p53-Itch interaction, colocalization and FLIP ubiquitination in chemosensitive but not chemoresistant ovarian cancer cells. Moreover, although activated Akt inhibited CDDP-induced FLIP degradation and apoptosis in sensitive cells, these responses were facilitated by dominant-negative Akt expression in chemoresistant cells. Inhibition of Akt function also facilitated p53-FLIP interaction and FLIP ubiquitination, which were attenuated by p53 silencing. These results suggest that Akt confers resistance, in part, by modulating CDDP-induced, p53-dependent FLIP ubiquitination. Understanding the precise etiology of chemoresistance may improve treatment for ovarian cancer.
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PMID:Akt promotes chemoresistance in human ovarian cancer cells by modulating cisplatin-induced, p53-dependent ubiquitination of FLICE-like inhibitory protein. 1980 16

Molecular regulation of p73, a p53 family member, remains unclear. Here we report that p73 expression is significantly regulated by cell densities. In particular, we found that p73alpha and p73beta are differentially regulated. While p73beta protein levels were inversely correlated with cell densities, p73alpha protein levels behaved oppositely. We further showed that density-dependent changes of p73alpha follow the same patterns as E2F-1 and TAp73 mRNA levels, suggesting transcriptional regulation. Our data also suggest that high levels of p73beta at lower densities may be due to increased protein stability. However, AIP-4/Itch appeared not to be involved in downregulation of p73beta at high densities. Moreover, we also found that subcellular location of p73 isoforms changes with the culture density increases. While high level of p73beta at low density was mainly presented in the nucleus, low levels of this protein at high densities were mainly in the cytosol. Taken together, these findings reveal a novel mechanism that differentially regulates p73 isoforms and underscores the role of cell-cell interaction in p73 regulation, which may advance our understanding of p73 expression and function in human cancers.
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PMID:Cell density-dependent regulation of p73 in breast cancer cells. 1988 66

It has been shown that MDM2 inhibits the transcriptional and pro-apoptotic activities of p73 but does not promote its proteasomal degradation. In this study, we found that MDM2 indirectly induces the degradation of p73 through the interaction with Itch in HeLa cells. During adriamycin (ADR)-mediated apoptosis, p53 and p73 were induced to stabilize in association with a significant reduction of MDM2 and Itch, suggesting that, in addition to Itch, MDM2 could also be involved in the stability control of p73. As expected, forced expression of MDM2 resulted in a remarkable reduction of p73. MDM2-mediated degradation of p73 was inhibited by MG-132. Intriguingly, siRNA-mediated knockdown of Itch significantly attenuated the negative effect of MDM2 on p73. Additionally, MDM2 bound to Itch in HeLa cells but not in H1299 cells. Collectively, our present findings suggest that MDM2 promotes Itch-mediated degradation of p73 through the interaction with Itch in HeLa cells.
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PMID:MDM2 promotes the proteasomal degradation of p73 through the interaction with Itch in HeLa cells. 2109 10

A new sunscreen ingredient, methoxycinnamidopropyl polysilsesquioxane (MCP-PSQ), which contains an UV-absorbing p-methoxycinnamoyl group, has been developed synthetically and evaluated using in vitro and in vivo approaches. Previous studies revealed that MCP-PSQ has a raising or boosting effect on the sun protection factor (SPF) of other sunscreen agents. In this study, we demonstrated that MCP-PSQ, an organic/inorganic hybrid compound, has photoprotective effects for human fibroblasts, and for hairless mouse and human skin. MCP-PSQ increases cell viability and suppresses the expression of p53 protein in fibroblasts after UV exposure. In addition, the numbers of sunburn cells and mast cells are reduced by topical application of MCP-PSQ on hairless mouse skin after UV irradiation. A 10% MCP-PSQ cream has higher and similar effects on SPF values for human skin compared to 5% titanium dioxide (TiO(2)) and 5% ethylhexyl methoxycinnamate (EHMC), respectively. The SPF value obtained using the MCP-PSQ cream did not drop after UV irradiation of the cream itself. However, higher dose of UV irradiation is required to guarantee the stability or photostability of the formulation. Further, there were no side effects such as erythema, edema, itch or tingling, suggesting that MCP-PSQ is a good sunscreen agent.
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PMID:Photoprotective effects of methoxycinnamidopropyl polysilsesquioxane. 2153 75


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