Cutl1: a Potential Target for Cancer Therapy

Cellular Signalling 25 (2013) 349–354

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Cellular Signalling

journal homepage: www.elsevier.com/locate/cellsig

Review Cutl1: A potential target for cancer therapy

Kuan-can Liu, Bao-shun Lin, Meng Zhao, Kai-yu Wang, Xiao-peng Lan ⁎

Institute for Laboratory Medicine, Fuzhou General Hospital, PLA, Fuzhou, Fujian 350025, PR China article info abstract

Article history: CDP, a key transcription regulator encoded by Cutl1 gene, has been demonstrated to be involved in repressing or Received 25 September 2012 promoting expression of target genes through its specific DNA-binding, meanwhile, the activity of CDP was Received in revised form 12 October 2012 influenced by some types of modifications including transcriptional, posttranscriptional, translational and post- Accepted 12 October 2012 translational modifications. In this review, we systematically analyzedtheroleofCDPinnormaldevelopment Available online 17 October 2012 and tumor progression, and then emphasized its interactors and downstream molecules. Eventually, we concluded that Cut1 could promote cancer progression and its down-regulating expression will be a promising strategy for Keywords: Cutl1 cancer therapy. Cancer progression © 2012 Elsevier Inc. All rights reserved. Cancer therapy Signal transduction

Contents

1. Introduction ...... 349 2. Variable activities of Cutl1modulated by modiﬁcations ...... 350 3. Interactions between Cutl1 and other proteins ...... 351 4. Roles of Cutl1 in normal development of tissues and organs ...... 351 5. Promoting or suppressing roles of Cutl1 in cancer? ...... 351 5.1. Relationships between Cutl1 and tumor progression ...... 352 5.2. Involvement of Cutl1 in cancer signal transduction pathways ...... 352 6. Conclusion and prospective ...... 352 Acknowledgments ...... 353 References ...... 353

1. Introduction located on chromosome 7 at band 22 through fluorescence in situ hy- bridization [2] and CDP proteins possessed four DNA-binding domain, Human Cutl1, also known as CutX1 or CCAAT displacement protein namely three CUT repeats (CR1,CR2 and CR3) and CUT homeodomain (cux/CDP), is a transcription factor involved in development and multiple (HD). However, the activity of CCAAT displacement simultaneously re- physiological processes. Cutl1 gene spans about 468 kb and generates quired sequence (CAAT or CGAT) and CR1+2 domains, but not CUT five distinct transcripts, which results from alternative transcription initi- homeodomain [3]. Meanwhile, another study demonstrated that a do- ation, splicing and polyadenylation [1]. Evidence showed that Cutl1 gene main at the extreme N-terminus of CDP proteins had the capability of inhibiting DNA-binding [4]. Previous studies indicated Cutl1 was closely Abbreviations: CDP, CCAAT displacement protein; HCC, human hepatocellular carci- correlated with development and its abnormity always resulted in ab- noma; LETFs, liver-enriched transcription factors; HNF, hepatocyte nuclear factor; Shh, normal generation of tissues and organs. Recently, emerging studies Sonic hedgehog; C/EBPα, CCAAT/enhancer-binding protein; MMTV, mouse mammary tumor virus; PCAF, p300/CREB-binding protein-associated factor; SATB1, special AT-rich showed Cutl1 was not only involved in developmental events, but also sequence binding protein 1; PyVLT antigen, Polyomavirus large T antigen; Csk, C-terminal in pathological process such as tumorigenesis and multiple signal trans- Src kinase; TNF, Tumor necrosis factors; TCRβ, T-cell receptor beta; IgH, Immunoglobulin duction pathways of cancer. heavy chain; CFTR, Cystic fibrosis transmembrane conductance regulator; CXCL1, Chemo- To better understand the roles of Cutl1 in cancer, we analyzed the kine (C-X-C motif) ligand 1; DKK2, Dickkopf homolog 2. modifications including transcriptional, posttranscriptional translational ⁎ Corresponding author at: Institute for Laboratory Medicine, Fuzhou General Hospital, PLA, Fuzhou, Fujian, PR China. Tel.: +86 591 22859490; fax: +86 591 83732129. and posttranslational modifications which could affect the activities E-mail address: [email protected] (X. Lan). of Cutl1, then systematically concluded the interactions between CDP

Fig. 1. Multiple levels of control on Cutl1 activities. proteins and other proteins, downstream molecules modulated by reporter assays. In the livers of developing mouse embryos and HCC Cutl1. Finally, we emphasized the signal transduction pathways which (human hepatocellular carcinoma) cells, four LETFs (liver-enriched tran- Cutl1 participated in and its effect in cancer cell behaviors including scription factors), including hepatocyte nuclear factor (HNF) 1α,HNF3β, proliferation, migration and growth, apoptosis and other aspects. HNF4α and C/EBPα (CCAAT/enhancer-binding protein), coordinately regulated miR122 expression. Meanwhile, they also demonstrated that 2. Variable activities of Cutl1modulated by modifications the repressed role of miR122 on Cutl1 through overexpression and knockdown methods, and Cutl1 expression was gradually silenced at Besides possessing five transcripts from different initiation or splicing posttranscriptional level during liver development [5]. and polyadenylation, there are other mechanisms, which containing trans- Additionally, other key modifications of Cutl1 derived from phosphor- lational and posttranslational modifications, regulate activities of CDP. ylation by kinase or de-phosphorylation by phosphatase [6], acetylation So far, only one report published their discovery of Cutl1 modification [7] and proteolytic cleavage. Previous reports have explored the role of at translational level. Qu and his colleagues found miR122, a liver-specific phosphorylation and de-phosphorylation in regulating Cutl1 activities. microRNA that expressed in mouse liver during embryogenesis, targeted Alain et al. found the capability of CDP-specific DNA binding increased Cutl1 and took inhibitive effect on Cutl1 translation through luciferase after phosphatase treatment by using nuclear extract from mammalian cells, meanwhile, they discovered that there are phosphorylation sites on the sequences of Cut repeat and occurrence of the phosphorylated Table 1 CDP proteins by casein kinase II resulted in inhibiting its DNA binding, in- Interactions between CDP and proteins. dicating transcriptional activity of CDP proteins was modulated by casein Interacted Role of complex References kinase II [8]. Besides casein kinase II, another study found CDP proteins proteins could also be directly phosphorylated by protein kinase A at serine Cdc25A Control the transitions from G1 to S phase and G2 to [6] 1215 and thereby regulated its effect on cell proliferation and motility, fi- M phase of cell cycle nally resulted in decreased DNA binding affinity of CDP proteins and PyVLT Induced leiomyomas and mammary tumors [11] diminished cell cycle progression and cell motility mediated by CDP pro- antigen teins, simultaneously, the downstream target of CDP proteins involved in HDAC1 Regulate CFTR expression [12] SATB1 Affected tissue-specific transcription of MMTV [13] proliferation and migration was also modulated after CDP phosphoryla- P107 and Represses osteocalcin [14] tion induced by protein kinase A [9]. On the other hand, cleavage of Cyclin A gene transcription CDP proteins could be induced by differentiation and thus produced a CBP and Acetylation of histone and CDP [7] novel dominant-negative isoform. Maitra et al. found the transcription PCAF CyclinA-Cdk1 Inhibited CDP/Cux stable DNA binding and prevented [15] of MMTV (mouse mammary tumor virus), a betaretrovirus responsible repression of the p21WAF1 expression for mammary-specific gene regulation, was repressed by CDP. However, AP-2 Suppress H3.2 gene expression [16] full-length of CDP could be processed to generate a 150 kDa isoform pRB Repress cell cycle regulated histone gene promoters [17] lacking C terminus within homeodomain, thereby decreased its binding fi Sox2 Unspeci ed [18]. to negative regulatory elements on MMTV and increased transcription Download English Version: https://daneshyari.com/en/article/10815321

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