DBC1/CCAR2 and CCAR1 Are Largely Disordered Proteins that Have Evolved from One Common Ancestor

Brunquell, Jessica; Jia, Yuan; Erwin, Aqeela; Westerheide, Sandy D.; Xue, Bin

doi:10.1155/2014/418458

Cited by 26 publications

(28 citation statements)

References 96 publications

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“…Also, enhancing sir‐2.1 activity through caloric restriction enhances the transcription of hsp‐70 (Raynes, Leckey, Nguyen, & Westerheide, 2012). Although C. elegans does not possess a known ortholog to AROS, CCAR2 does have a worm ortholog named CCAR‐1, previously called LST‐3 (Brunquell, Yuan, Erwin, Westerheide, & Xue, 2014). We were therefore interested in determining whether negative regulation of the HSR by the SIRT1 modulator CCAR2 also occurs in the worm, and how this interaction would impact stress‐related responses and longevity.…”

Section: Introductionmentioning

confidence: 99%

CCAR‐1 is a negative regulator of the heat‐shock response in Caenorhabditis elegans

et al. 2018

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Defects in protein quality control during aging are central to many human diseases, and strategies are needed to better understand mechanisms of controlling the quality of the proteome. The heat‐shock response (HSR) is a conserved survival mechanism mediated by the transcription factor HSF1 which functions to maintain proteostasis. In mammalian cells, HSF1 is regulated by a variety of factors including the prolongevity factor SIRT1. SIRT1 promotes the DNA‐bound state of HSF1 through deacetylation of the DNA‐binding domain of HSF1, thereby enhancing the HSR. SIRT1 is also regulated by various factors, including negative regulation by the cell‐cycle and apoptosis regulator CCAR2. CCAR2 negatively regulates the HSR, possibly through its inhibitory interaction with SIRT1. We were interested in studying conservation of the SIRT1/CCAR2 regulatory interaction in Caenorhabditis elegans, and in utilizing this model organism to observe the effects of modulating sirtuin activity on the HSR, longevity, and proteostasis. The HSR is highly conserved in C. elegans and is mediated by the HSF1 homolog, HSF‐1. We have uncovered that negative regulation of the HSR by CCAR2 is conserved in C. elegans and is mediated by the CCAR2 ortholog, CCAR‐1. This negative regulation requires the SIRT1 homolog SIR‐2.1. In addition, knockdown of CCAR‐1 via ccar‐1 RNAi works through SIR‐2.1 to enhance stress resistance, motility, longevity, and proteostasis. This work therefore highlights the benefits of enhancing sirtuin activity to promote the HSR at the level of the whole organism.

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Section: Introductionmentioning

confidence: 99%

CCAR‐1 is a negative regulator of the heat‐shock response in Caenorhabditis elegans

et al. 2018

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“…Through different protein-protein interactions, CCAR1 can activate multiple downstream targets implicated in proliferation, apoptosis and differentiation (Kim et al, 2008;Lu et al, 2012;Ou et al, 2009). CCAR1 possesses a DNAbinding domain, a RNA-binding domain and several protein interaction domains, indicating that CCAR1 might participate in multiple processes (Brunquell et al, 2014). However, functions of CCAR1 in processes other than transcriptional regulation still remain undiscovered.…”

Section: Introductionmentioning

confidence: 99%

CCAR-1 affects hemidesmosome biogenesis by regulating unc-52/perlecan alternative splicing in the C. elegans epidermis

Zhu

Jiang

et al. 2018

Journal of Cell Science

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Hemidesmosomes are epithelial-specific attachment structures that maintain tissue integrity and resist tension. Despite their importance, how hemidesmosomes are regulated at the post-transcriptional level is poorly understood. hemidesmosomes (CeHDs) have a similar structure and composition to their mammalian counterparts, making an ideal model for studying hemidesmosomes. Here, we focus on the transcription regulator CCAR-1, identified in a previous genetic screen searching for enhancers of mutations in the conserved hemidesmosome component VAB-10A (known as plectin in mammals). Loss of CCAR-1 function in a background results in CeHD disruption and muscle detachment from the epidermis. CCAR-1 regulates CeHD biogenesis, not by controlling the transcription of CeHD-related genes, but by affecting the alternative splicing of (known as perlecan or HSPG2 in mammals), the predicted basement extracellular matrix (ECM) ligand of CeHDs. CCAR-1 physically interacts with HRP-2 (hnRNPR in mammals), a splicing factor known to mediate alternative splicing to control the proportions of different UNC-52 isoforms and stabilize CeHDs. Our discovery underlines the importance of post-transcriptional regulation in hemidesmosome reorganization. It also uncovers previously unappreciated roles of CCAR-1 in alternative splicing and hemidesmosome biogenesis, shedding new light on the mechanisms through which mammalian CCAR1 functions in tumorigenesis.

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“…Although CARP-1/CCAR1 and DBC1 proteins are paralogs, a recent report revealed that both the DBC1 and CARP-1/CCAR1 are largely disordered proteins that evolved from a single common ancestor, the nematode Caenorhabditis elegans protein lateral signaling target (LST)-3 [24]. DBC1 emerged later in evolution than CARP-1/CCAR1 and first appeared in Danio rerio (zebrafish).…”

Section: Introductionmentioning

confidence: 99%

“…DBC1 emerged later in evolution than CARP-1/CCAR1 and first appeared in Danio rerio (zebrafish). Interestingly, the DBC1 gene is not present in insects, amphibians, or birds [24]. Nevertheless, a synergistic co-regulation of CARP-1/CCAR1 by DBC1 in mediating ERα target gene transcription in MCF7 and T47D HBC cells was noted in a recent study [25].…”

Section: Introductionmentioning

confidence: 99%

CARP-1 / CCAR1: A biphasic regulator of cancer cell growth and apoptosis

2015

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Targeted cancer therapy using small molecule inhibitors (SMIs) has been useful in targeting the tumor cells while sparing the normal cells. Despite clinical success of many targeted therapies, their off-target effects and development of resistance are emerging as significant and challenging problems. Thus, there is an urgent need to identify targets to devise new means to treat cancers and their drug-resistant phenotypes. CARP-1/CCAR1 (Cell division cycle and apoptosis regulator 1), a peri-nuclear phospho-protein, plays a dynamic role in regulating cell growth and apoptosis by serving as a co-activator of steroid/thyroid nuclear receptors, β-catenin, Anaphase Promoting Complex/Cyclosome (APC/C) E3 ligase, and tumor suppressor p53. CARP-1/CCAR1 also regulates chemotherapy-dependent apoptosis. CARP-1/CCAR1 functional mimetics (CFMs) are a novel SMIs of CARP-1/CCAR1 interaction with APC/C. CFMs promote apoptosis in a manner independent of p53. CFMs are potent inhibitors of a variety of cancer cells including the drug (Adriamycin or Tamoxifen)-resistant breast cancer cells but not the immortalized breast epithelial cells, while a nano-lipid formulation of the lead compound CFM-4 improves its bioavailability and efficacy in vivo when administered orally. This review focuses on the background and pleiotropic roles of CARP-1/CCAR1 as well as its apoptosis signaling mechanisms in response to chemotherapy in cancer cells.

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DBC1/CCAR2 and CCAR1 Are Largely Disordered Proteins that Have Evolved from One Common Ancestor

Cited by 26 publications

References 96 publications

CCAR‐1 is a negative regulator of the heat‐shock response in Caenorhabditis elegans

CCAR‐1 is a negative regulator of the heat‐shock response in Caenorhabditis elegans

CCAR-1 affects hemidesmosome biogenesis by regulating unc-52/perlecan alternative splicing in the C. elegans epidermis

CARP-1 / CCAR1: A biphasic regulator of cancer cell growth and apoptosis

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