Metastasis-associated Protein 1 Drives Tumor Cell Migration and Invasion through Transcriptional Repression of RING Finger Protein 144A

Marzook, Hezlin; Li, Da‐Qiang; Nair, Vasudha S.; Mudvari, Prakriti; Reddy, Sirigiri Divijendra Natha; Pakala, Suresh B.; Santhoshkumar, T.R.; Pillai, M. Radhakrishna; Kumar, Rakesh

doi:10.1074/jbc.m111.314088

Cited by 17 publications

(11 citation statements)

References 48 publications

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“…It will be very interesting to determine whether VCP is also involved in RNF144A-DNA-PKcs regulation in the future. A previous study suggested that RNF144A suppresses tumor migration and invasion (8). Our study identifies a previously unidentified role for RNF144A in apoptosis induction through suppression of the prosurvival signaling function of DNA-PKcs.…”

Section: Discussionsupporting

confidence: 54%

“…RNF144A is able to interact with E2-conjugating enzymes UbcH7 and UbcH8 through its RING1 domain, and mutations on IBR or RING2 reduce this E2-E3 interaction (7). In addition, RNF144A is transcriptionally repressed by metastasis-associated protein 1 and inhibits migration and invasion in breast tumor cells (8). However, whether RNF144A is involved in apoptosis and DNA damage response (DDR) remains unexplored.…”

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confidence: 99%

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RNF144A, an E3 ubiquitin ligase for DNA-PKcs, promotes apoptosis during DNA damage

Ho¹,

Mahanic

Lee

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Several ring between ring fingers (RBR) -domain proteins, such as Parkin and Parc, have been shown to be E3 ligases involved in important biological processes. Here, we identify a poorly characterized RBR protein, Ring Finger protein 144A (RNF144A), as the first, to our knowledge, mammalian E3 ubiquitin ligase for DNAPKcs. We show that DNA damage induces RNF144A expression in a p53-dependent manner. RNF144A is mainly localized in the cytoplasmic vesicles and plasma membrane and interacts with cytoplasmic DNA-dependent protein kinase, catalytic subunit (DNA-PKcs). DNA-PKcs plays a critical role in the nonhomologous end-joining DNA repair pathway and provides prosurvival signaling during DNA damage. We show that RNF144A induces ubiquitination of DNA-PKcs in vitro and in vivo and promotes its degradation. Depletion of RNF144A leads to an increased level of DNA-PKcs and resistance to DNA damaging agents, which is reversed by a DNA-PK inhibitor. Taken together, our data suggest that RNF144A may be involved in p53-mediated apoptosis through down-regulation of DNA-PKcs when cells suffer from persistent or severe DNA damage insults.endosome | DDR | transmembrane domain R ing Finger protein 144A (RNF144A) and RNF144B belong to the RNF144 family and are very conserved in higher eukaryotes. Both proteins contain an RING1-in between rings (IBR) -RING2 [termed the ring between ring fingers (RBR)] domain in the N terminus and a potential single-transmembrane (TM) domain in the C terminus. RBR domain-containing proteins usually possess an E3 ubiquitin ligase activity and are involved in regulation of the cell cycle and apoptosis (1-3). These proteins function like RING (Really Interesting New Gene)/HECT (Homologous to the E6AP Carboxyl Terminus) hybrids (i.e., they use their RING1 to bind E2s) but then transfer ubiquitin onto a conserved cysteine residue in the RING2 domain through a thioester linkage similar to the E3 thioester-linked ubiquitin intermediates in HECT-type E3 ligases (4). It has been shown that DNA damage induces RNF144B expression to promote cell apoptosis through regulation of the stability of p21 (5), BAX (1), and p73 (6). RNF144B shares 71% homology of amino acids with RNF144A.

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Section: Discussionsupporting

confidence: 54%

mentioning

confidence: 99%

RNF144A, an E3 ubiquitin ligase for DNA-PKcs, promotes apoptosis during DNA damage

Ho¹,

Mahanic

Lee

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Recent reports also identified MTA1-NuRD as a new HIC1 corepressor that targets the HiREs (HIC1 binding sites) in the promoters of Cyclin D1 [90], p57KIP2 [90], and EphA2 [91] in WI38 cells. In addition, MTA1 was also observed to be involved in the transcriptional repression of Six3 [29,92], p21 WAF1 [37], MMP-9 [93], RNF114A [94], SMAD7 [95], and PTEN [93] via NuRD.…”

Section: Mta1 As a Co-repressor Of Gene Transcription Through The Nurmentioning

confidence: 97%

Subcellular localization of MTA proteins in normal and cancer cells

Liu

Wang

Huang

et al. 2014

Cancer Metastasis Rev

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The subcellular localization of a protein is closely linked to and indicates its function. The metastatic tumor antigen (MTA) family has been under continuous investigation since its identification two decades ago. MTA1, MTA2, and MTA3 are the main members of the MTA family. MTA1, as the representative member of this family, has been shown to be widely expressed in both embryonic and adult tissues, as well as in normal and cancerous conditions, indicating that MTA1 has functions both in physiological and pathological contexts. MTA1 is expressed at a higher level in most cancers than in their normal tissue counterparts. Even in normal cells, MTA1 levels vary a great deal from tissue to tissue. Importantly, MTA1 shows a multiple localization pattern in the cell, as do MTA2 and MTA3. Different MTA components in different subcellular compartments may exert different molecular functions in the cell. Previous studies revealed that MTA1 and MTA2 are predominately localized to the nucleus, while MTA3 is observed in both the nucleus and cytoplasm. Recent studies have reported that MTA1 is located in the nucleus, cytoplasm, and the nuclear envelope. In the nucleus, MTA1 dynamically interacts with chromatin in a MTA1-K532 methylation-dependent manner, whereas cytoplasmic MTA1 binds to the microtubule skeleton. MTA1 also shows a dynamic distribution during the cell cycle. Further investigations are needed to identify the exact subcellular localizations of MTA proteins. We review the sub-cellular localization patterns of the MTA family members and give a comprehensive overview of their respective molecular activities in multiple contexts.

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“…Earlier studies have demonstrated that MTA1 forms a corepressor complex with HDAC1/2 and is recruited to the target gene promoters, thereby repressing gene transcription (29). For example, the MTA1⅐HDAC2 complex was identified as a transcriptional corepressor of number of tumor suppressor genes such as BRAC1, p21WAF1, and RNF144, where the MTA1⅐HDAC2 complex recruits onto their promoters and down-regulates the expression of these genes, leading to accelerated tumor growth and metastasis (32,41,42). In this study, we identified MTA1 as a transcriptional corepressor of the tumor suppressor gene PTEN, but contrary to earlier studies, for the first time, we found that MTA1 but not MTA2 associates with class II HDAC4s and identified the first target of the MTA1⅐HDAC4 containing the NuRD complex, the PTEN.…”

Section: Mta1 Expression Inversely Correlates With Pten Expresmentioning

confidence: 99%

Metastasis-associated Protein 1/Histone Deacetylase 4-Nucleosome Remodeling and Deacetylase Complex Regulates Phosphatase and Tensin Homolog Gene Expression and Function

Reddy

Pakala

Molli

et al. 2012

Journal of Biological Chemistry

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Background: MTA1 is overexpressed in several advanced cancers, but its role in cell survival signaling is yet to be elucidated. Results: MTA1 transcriptionally represses the expression of PTEN and, consequently, PTEN-dependent signaling and functions. Conclusion: PTEN is a target of the MTA1/HDAC4-containing NuRD complex. Significance: This study provides a novel mechanistic insight into the regulation of PTEN by MTA1.

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Metastasis-associated Protein 1 Drives Tumor Cell Migration and Invasion through Transcriptional Repression of RING Finger Protein 144A

Cited by 17 publications

References 48 publications

RNF144A, an E3 ubiquitin ligase for DNA-PKcs, promotes apoptosis during DNA damage

RNF144A, an E3 ubiquitin ligase for DNA-PKcs, promotes apoptosis during DNA damage

Subcellular localization of MTA proteins in normal and cancer cells

Metastasis-associated Protein 1/Histone Deacetylase 4-Nucleosome Remodeling and Deacetylase Complex Regulates Phosphatase and Tensin Homolog Gene Expression and Function

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