Transcriptional activation of p62/A170/ZIP during the formation of the aggregates: possible mechanisms and the role in Lewy body formation in Parkinson's disease

Nakaso, Kazuhiro; Yoshimoto, Yoshihide; Nakano, Tetsuo; Takeshima, Takao; Fukuhara, Yoko; Yasui, Kenichi; Araga, Shigeru; Yanagawa, Toru; Ishii, Tetsuro; Nakashima, Kenichiro

doi:10.1016/j.brainres.2004.03.029

Cited by 127 publications

(93 citation statements)

References 32 publications

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“…Secondly, besides LC3, p62 contains domains that interact with several signaling molecules, indicating that p62 may have other functions with regard to its role in autophagy [45] . Finally, p62 can be transcriptionally upregulated under certain conditions [46] . Given these potential pitfalls, to monitor autophagic flux it is recommended that the measurement of the p62 level be performed in combination with other methods such as LC3-II turnover.…”

Section: Methods For Monitoring Autophagic Fluxmentioning

confidence: 99%

Why should autophagic flux be assessed?

et al. 2013

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As autophagy is involved in cell growth, survival, development and death, impaired autophagic flux has been linked to a variety of human pathophysiological processes, including neurodegeneration, cancer, myopathy, cardiovascular and immune-mediated disorders. There is a growing need to identify and quantify the status of autophagic flux in different pathological conditions. Given that autophagy is a highly dynamic and complex process that is regulated at multiple steps, it is often assessed accurately. This perspective review article will focus on the autophagic flux defects in different human disorders and update the current methods of monitoring autophagic flux. This knowledge is essential for developing autophagy-related therapeutics for treating the diseases.

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Section: Methods For Monitoring Autophagic Fluxmentioning

confidence: 99%

Why should autophagic flux be assessed?

et al. 2013

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“…With regard to protein synthesis, it is worth noting that this can be monitored through a nonradioactive method. 324 Finally, SQSTM1 may be transcriptionally upregulated under certain conditions, 227,325 further complicating the interpretation of results. For example, SQSTM1 upregulation, and at least transient increases in the amount of SQSTM1, is seen in some situations where there is an increase in autophagic flux.…”

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confidence: 99%

Guidelines for the use and interpretation of assays for monitoring autophagy

Klionsky¹,

Abdalla²,

Abeliovich³

et al. 2012

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In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

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“…The expression of p62 is induced by the aggregation of unfolded proteins. This aggregation may be launched by changes in cellular redox state, for example during oxidative stress or the inhibition of proteasomal activity by overload of ubiquitin-proteasome system (UPS) (Kuusisto et al, 2001b;Thompson et al, 2003;Nakaso et al, 2004). Autophagy may be involved in the clearance of such protein aggregates, with p62 playing an active role in the process.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia-activated autophagy accelerates degradation of SQSTM1/p62

et al. 2008

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Sequestosome 1 (SQSTM1/p62) is a multifunctional protein involved in signal transduction, protein degradation and cell transformation. Hypoxia is a common feature of solid tumours that promotes cancer progression. Here, we report that p62 is downregulated in hypoxia in carcinoma cells and that the expression is rapidly restored in response to reoxygenation. The hypoxic p62 downregulation did not occur at the mRNA level and was independent of the hypoxic signal mediators hypoxiainducible factor (HIF) and von Hippel-Lindau tumour suppressor protein as well as the activity of HIF-prolyl hydroxylases and was not mediated by proteosomal destruction. Autophagy was activated in hypoxia and was required for p62 degradation. The hypoxic degradation of p62 was blocked by autophagy inhibitors as well as by the attenuation of Atg8/LC3 expression. Downregulation of p62 was required for hypoxic extracellular regulated kinase (ERK)-1/2 phosphorylation. Attenuation of p62 in normoxia activated and forced expression of p62 in hypoxia blocked the activation of ERK-1/2. The results demonstrate that hypoxic activation of autophagy induces clearance of p62 protein and implies a role for p62 in the regulation of hypoxic cancer cell survival responses.

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Transcriptional activation of p62/A170/ZIP during the formation of the aggregates: possible mechanisms and the role in Lewy body formation in Parkinson's disease

Cited by 127 publications

References 32 publications

Why should autophagic flux be assessed?

Why should autophagic flux be assessed?

Guidelines for the use and interpretation of assays for monitoring autophagy

Hypoxia-activated autophagy accelerates degradation of SQSTM1/p62

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