Ataxin-3 like (ATXN3L), a member of the Josephin family of deubiquitinating enzymes, promotes breast cancer proliferation by deubiquitinating Krüppel-like factor 5 (KLF5)

Ge, Fei; Chen, Wenlin; Qin, Junying; Zhou, Zhongmei; Liu, Rong; Liu, Linlin; Tan, Jian; Zou, Tianning; Li, Hongyuan; Ren, Guosheng; Chen, Ceshi

doi:10.18632/oncotarget.4128

Cited by 40 publications

(34 citation statements)

References 26 publications

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“…Given the important role of p53 in neurodegenerative diseases and cancer, it is thus a likely possible candidate. Recent studies have reported that ATX-3 and ATX-3 like are involved in gastric cancer [63] and breast cancer [64], supporting the association of the Josephin family of DUBs with cancer. Importantly, aberrant activation of the p53 pathway has previously been reported in both MJD patient brain tissues and transgenic animal disease models [65–69], and elevated p53 level was observed in MJD transgenic mice [65].…”

Section: Discussionmentioning

confidence: 89%

The Machado–Joseph Disease Deubiquitinase Ataxin-3 Regulates the Stability and Apoptotic Function of p53

Guan

et al. 2016

PLoS Biol

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As a deubiquitinating enzyme (DUB), the physiological substrates of ataxin-3 (ATX-3) remain elusive, which limits our understanding of its normal cellular function and that of pathogenic mechanism of spinocerebellar ataxia type 3 (SCA3). Here, we identify p53 to be a novel substrate of ATX-3. ATX-3 binds to native and polyubiquitinated p53 and deubiquitinates and stabilizes p53 by repressing its degradation through the ubiquitin (Ub)-proteasome pathway. ATX-3 deletion destabilizes p53, resulting in deficiency of p53 activity and functions, whereas ectopic expression of ATX-3 induces selective transcription/expression of p53 target genes and promotes p53-dependent apoptosis in both mammalian cells and the central nervous system of zebrafish. Furthermore, the polyglutamine (polyQ)-expanded ATX-3 retains enhanced interaction and deubiquitination catalytic activity to p53 and causes more severe p53-dependent neurodegeneration in zebrafish brains and in the substantia nigra pars compacta (SNpc) or striatum of a transgenic SCA3 mouse model. Our findings identify a novel molecular link between ATX-3 and p53-mediated cell death and provide an explanation for the direct involvement of p53 in SCA3 disease pathogenesis.

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Section: Discussionmentioning

confidence: 89%

The Machado–Joseph Disease Deubiquitinase Ataxin-3 Regulates the Stability and Apoptotic Function of p53

Guan

et al. 2016

PLoS Biol

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“…Scale bar: 0.2 amino acid changes per site. (Frontelo et al, 2007;Nuez et al, 1995;Ouyang et al, 1998;Perkins et al, 1995;Siatecka et al, 2007;Zhang et al, 2001b) (Anderson et al, 1995;Basu et al, 2005;Carlson et al, 2006;Kuo et al, 1997a;Kuo et al, 1997b;Lee et al, 2006;Nakagawa et al, 2008;Wang et al, 2013;Wani et al, 1999a,b;Wu et al, 2005;Xie et al, 2011;Zhang et al, 2004 (Chaib et al, 2001;Chen et al, 2002;Chen et al, 2005a;Conkright et al, 1999;Du et al, 2007;Ge et al, 2015;He et al, 2009;Liu et al, 2010;McConnell et al, 2009;McConnell et al, 2007;Nakagawa et al, 2008;Nandan et al, 2010;Nandan et al, 2008;Oishi et al, 2008;Oishi et al, 2005;Qin et al, 2015;Shindo et al, 2002;Shinoda et al, 2008;Takeda et al, 2010;Tong et al, 2006;Wan et al, 2008;...…”

Section: Other Endoderm-derived Organsmentioning

confidence: 99%

Krüppel-like factors in mammalian stem cells and development

2017

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Krüppel-like factors (KLFs) are a family of zinc-finger transcription factors that are found in many species. Recent studies have shown that KLFs play a fundamental role in regulating diverse biological processes such as cell proliferation, differentiation, development and regeneration. Of note, several KLFs are also crucial for maintaining pluripotency and, hence, have been linked to reprogramming and regenerative medicine approaches. Here, we review the crucial functions of KLFs in mammalian embryogenesis, stem cell biology and regeneration, as revealed by studies of animal models. We also highlight how KLFs have been implicated in human diseases and outline potential avenues for future research.

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“…KLF5 (Krüppel-like factor 5) is a zinc finger transcription factor that is highly expressed in basal-like breast cancer and promotes cell proliferation, survival, migration, and tumorigenesis [61]. A recent study identified ATXN3L, a member of the MJD family, as a KLF5 DUB by siRNA screening [61].…”

Section: Breast Cancer-promoting Dubsmentioning

confidence: 99%

“…A recent study identified ATXN3L, a member of the MJD family, as a KLF5 DUB by siRNA screening [61]. ATXN3L directly binds, deubiquitinates, and stabilizes KLF5.…”

Section: Breast Cancer-promoting Dubsmentioning

confidence: 99%

“…ATXN3L directly binds, deubiquitinates, and stabilizes KLF5. Knockdown of ATXN3L decreased KLF5 protein levels and inhibited the proliferation of breast cancer cells [61]. Another KLF5 DUB that stood out in siRNA screening was BAP1 (BRCA1-associated protein 1), which also directly binds KLF5 and stabilizes KLF5 through deubiquitination [62].…”

Section: Breast Cancer-promoting Dubsmentioning

confidence: 99%

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The role of deubiquitinases in breast cancer

Xiao

Zhang

2016

Cancer Metastasis Rev

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Although growing numbers of oncoproteins and pro-metastatic proteins have been extensively characterized, many of these tumor-promoting proteins are not good drug targets, which represents a major barrier to curing breast cancer and other cancers. There is a need, therefore, for alternative therapeutic approaches to destroying cancer-promoting proteins. The human genome encodes approximately 100 deubiquitinating enzymes (DUBs, also called deubiquitinases), which are amenable to pharmacologic inhibition by small molecules. By removing monoubiquitin or polyubiquitin chains from the target protein, DUBs can modulate the degradation, localization, activity, trafficking, and recycling of the substrate, thereby contributing substantially to the regulation of cancer proteins and pathways. Targeting certain DUBs may lead to destabilization or functional inactivation of some key oncoproteins or prometastatic proteins, including non-druggable ones, which will provide therapeutic benefits to cancer patients. In breast cancer, growing numbers of DUBs are found to be aberrantly expressed. Depending on their substrates, specific DUBs can either promote or suppress mammary tumors. In this article, we review the role and mechanisms of action of DUBs in breast cancer, and discuss the potential of targeting DUBs for cancer treatment.

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Ataxin-3 like (ATXN3L), a member of the Josephin family of deubiquitinating enzymes, promotes breast cancer proliferation by deubiquitinating Krüppel-like factor 5 (KLF5)

Cited by 40 publications

References 26 publications

The Machado–Joseph Disease Deubiquitinase Ataxin-3 Regulates the Stability and Apoptotic Function of p53

The Machado–Joseph Disease Deubiquitinase Ataxin-3 Regulates the Stability and Apoptotic Function of p53

Krüppel-like factors in mammalian stem cells and development

The role of deubiquitinases in breast cancer

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