Cisplatin transiently up-regulates hHR23 expression through enhanced translational efficiency in A549 adenocarcinoma cells

Shen, Yu-Han; Chen, Bo-Rong; Cherng, Shur Hueih; Chueh, Pin Ju; Tan, X.; Lin, Yun‐Wei; Lin, Jin-Ching; Chuang, Shiow-Shuh

doi:10.1016/j.toxlet.2011.06.028

Cited by 13 publications

(13 citation statements)

References 24 publications

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“…There is evidence both for and against a role of the UBA/UBL adaptor proteins hHR23A and hHR23B in the degradation of p53. 40, 41, 42, 43 Mdm2 can promote the ubiquitin-independent association of p53 with the proteasome. 46 There may be handover of ubiquitinated p53 from Mdm2 to S5a.…”

Section: Discussionmentioning

confidence: 99%

“…40 However, in other studies, their depletion resulted in a decrease in p53 levels. 41, 42, 43 p53 and Mdm2 have been reported to bind to a number of proteasomal subunits in a ubiquitin-independent manner. 44, 45, 46, 47, 48 Mdm2 promotes ubiquitination-independent association of p53 with the proteasome, but an additional step requiring the ubiquitin ligase activity of Mdm2 is necessary for p53 degradation.…”

Section: Introductionmentioning

confidence: 99%

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The degradation of p53 and its major E3 ligase Mdm2 is differentially dependent on the proteasomal ubiquitin receptor S5a

et al. 2013

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p53 and its major E3 ligase Mdm2 are both ubiquitinated and targeted to the proteasome for degradation. Despite the importance of this in regulating the p53 pathway, little is known about the mechanisms of proteasomal recognition of ubiquitinated p53 and Mdm2. In this study, we show that knockdown of the proteasomal ubiquitin receptor S5a/PSMD4/Rpn10 inhibits p53 protein degradation and results in the accumulation of ubiquitinated p53. Overexpression of a dominant-negative deletion of S5a lacking its ubiquitin-interacting motifs (UIM)s, but which can be incorporated into the proteasome, also causes the stabilization of p53. Furthermore, small-interferring RNA (siRNA) rescue experiments confirm that the UIMs of S5a are required for the maintenance of low p53 levels. These observations indicate that S5a participates in the recognition of ubiquitinated p53 by the proteasome. In contrast, targeting S5a has no effect on the rate of degradation of Mdm2, indicating that proteasomal recognition of Mdm2 can be mediated by an S5a-independent pathway. S5a knockdown results in an increase in the transcriptional activity of p53. The selective stabilization of p53 and not Mdm2 provides a mechanism for p53 activation. Depletion of S5a causes a p53-dependent decrease in cell proliferation, demonstrating that p53 can have a dominant role in the response to targeting S5a. This study provides evidence for alternative pathways of proteasomal recognition of p53 and Mdm2. Differences in recognition by the proteasome could provide a means to modulate the relative stability of p53 and Mdm2 in response to cellular signals. In addition, they could be exploited for p53-activating therapies. This work shows that the degradation of proteins by the proteasome can be selectively dependent on S5a in human cells, and that this selectivity can extend to an E3 ubiquitin ligase and its substrate.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The degradation of p53 and its major E3 ligase Mdm2 is differentially dependent on the proteasomal ubiquitin receptor S5a

et al. 2013

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“…The exact role of XPC in lung cancer chemoresistance remains unclear. Treatment with cisplatin up-regulates expression of both XPC and its associated hHR23B protein in A549 lung adenocarcinoma cells, with a parallel increase in platinum resistance [57]. The XPC polymorphism Lys939Gln was associated with a decreased response to cisplatin therapy in a retrospective study of 96 NSCLC patients [58].…”

Section: Nucleotide Excision Repair (Ner)mentioning

confidence: 99%

The role of DNA repair pathways in cisplatin resistant lung cancer

O’Grady

Finn

Cuffe

et al. 2014

Cancer Treatment Reviews

124

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“…Moreover, it has been shown that cisplatin exposure results in up-regulation of HR23/Rad23, a protein participating in lesion recognition during DNA repair by NER; induction of the protein appears to involve MEK/ERK because it is reduced by exposure to the MEK inhibitor U0126 [61].…”

Section: The Erk Cascade and Resistance To Platinum Compoundsmentioning

confidence: 99%

Modulation of Sensitivity to Antitumor Agents by Targeting the MAPK Survival Pathway

Cossa¹,

Gatti²,

Cassinelli³

et al. 2013

Current Pharmaceutical Design

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Mitogen-activated protein kinases (MAPK) are involved in a complex network which regulates a variety of cellular processes including proliferation, survival and death. The molecular characterization of the pathway has shown aberrant activation in several human tumors, due to the deregulation of receptor tyrosine kinases or to mutations of pathway components. Progress in understanding the MAPK network has led to the development of target-specific agents in clinical trials. The relevance of MAPK in response and resistance to antitumor agents has been recognized, although the outcome of MAPK activation can vary depending on the molecular background of tumor cells and on the type of activated kinase. The canonical cascade of MAPK, i.e., depending on the Extracellular Signal-Regulated Kinases (ERK), can act in protective signalling pathways, thereby limiting DNA damage. Since tumor cell survival can be sustained by ERK and cross talk of ERK with other pathways, modulation of sensitivity to antitumor agents by targeting the ERK cascade appears to be an amenable approach. Indeed, ERK play a role in resistance to both cytotoxic and target-specific agents. Preclinical studies support the relevance of drug combination approaches to enhance the efficacy of antitumor treatments. Combinations of pharmacological inhibitors of the ERK cascade and conventional or target-specific antitumor agents may be helpful in an attempt to overcome drug resistance. A deeper understanding of the genetic alterations of tumor cells and of tumor heterogeneity as well as of drug resistance mechanisms is expected to contribute to the rational design of MAPK-mediated drug combinations that will lead to reversal of drug resistance.

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Cisplatin transiently up-regulates hHR23 expression through enhanced translational efficiency in A549 adenocarcinoma cells

Cited by 13 publications

References 24 publications

The degradation of p53 and its major E3 ligase Mdm2 is differentially dependent on the proteasomal ubiquitin receptor S5a

The degradation of p53 and its major E3 ligase Mdm2 is differentially dependent on the proteasomal ubiquitin receptor S5a

The role of DNA repair pathways in cisplatin resistant lung cancer

Modulation of Sensitivity to Antitumor Agents by Targeting the MAPK Survival Pathway

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