Bmcc1s, a Novel Brain-Isoform of Bmcc1, Affects Cell Morphology by Regulating MAP6/STOP Functions

Arama, Jessica; Boulay, Anne; Bosc, Christophe; Delphin, Christian; Loew, Damarys; Rostaing, Philippe; Amigou, Edwige; Ezan, Pascal; Wingertsmann, Laure; Guillaud, Laurent; Andrieux, Annie; Giaume, Christian; Cohen-Salmon, Martine

doi:10.1371/journal.pone.0035488

Cited by 16 publications

(19 citation statements)

References 36 publications

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“…contains several alternatively spliced isoforms (25)(26)(27)(28), one of which is ∼3 kb shorter than the PRUNE2 full-length sequence identified here (presumably the canonical gene) and is found in human adult nerve cells (25), with a related mouse brain-specific isoform (26); thus, other tissue-specific isoforms with different functions may perhaps exist. Tumor suppressor genes have long been shown to affect cancer growth in the classic two-hit hypothesis (29,30).…”

Section: Levels Of Pca3 and Prune2 Inversely Correlate In Human Prostmentioning

confidence: 72%

PRUNE2 is a human prostate cancer suppressor regulated by the intronic long noncoding RNA PCA3

Salameh

Lee

Cardó-Vila

et al. 2015

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

236

191

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Prostate cancer antigen 3 (PCA3) is the most specific prostate cancer biomarker but its function remains unknown. Here we identify PRUNE2, a target protein-coding gene variant, which harbors the PCA3 locus, thereby classifying PCA3 as an antisense intronic long noncoding (lnc)RNA. We show that PCA3 controls PRUNE2 levels via a unique regulatory mechanism involving formation of a PRUNE2/PCA3 double-stranded RNA that undergoes adenosine deaminase acting on RNA (ADAR)-dependent adenosine-to-inosine RNA editing. PRUNE2 expression or silencing in prostate cancer cells decreased and increased cell proliferation, respectively. Moreover, PRUNE2 and PCA3 elicited opposite effects on tumor growth in immunodeficient tumor-bearing mice. Coregulation and RNA editing of PRUNE2 and PCA3 were confirmed in human prostate cancer specimens, supporting the medical relevance of our findings. These results establish PCA3 as a dominant-negative oncogene and PRUNE2 as an unrecognized tumor suppressor gene in human prostate cancer, and their regulatory axis represents a unique molecular target for diagnostic and therapeutic intervention.S everal lines of evidence demonstrate that long noncoding RNAs (lncRNAs) are functional in carcinogenesis through regulatory mechanisms such as promoter looping, alternative splicing, antisense gene silencing, transcriptional regulation, and DNA repair, thus potentially serving as tumor markers. A few lncRNA species have emerged as potential prostate cancer biomarkers such as prostate cancer gene expression marker-1 (PCGEM1) and prostate cancer noncoding RNA1 (PRNCR1), which enhance androgen receptor (AR)-dependent gene activation, and prostate cancer-associated ncRNA transcript-1 (PCAT1), which silences BRCA2 via posttranscriptional homologous recombination (1). Notably, the most specific biomarker in human prostate cancer identified to date is an lncRNA, prostate cancer antigen 3 (PCA3, also known as PCA3 DD3 or DD3 PCA3 ), which is up-regulated in human prostate cancer (2). Since its discovery more than 15 y ago, PCA3 has been extensively investigated (3) and has been approved for clinical applications to aid the diagnosis of prostate cancer in both the European Union and the United States. Paradoxically-despite its striking clinical specificity-the inherent cellular role of the lncRNA PCA3 in human prostate cancer, if any, remains completely unknown (1). Here we report a unique biological function for PCA3. Within a single functional genetic unit, we show that PCA3 is an antisense intronic lncRNA that down-regulates an as yet unrecognized tumor suppressor gene, a human homolog of the Drosophila prune gene, PRUNE2, through a process that involves RNA editing mediated by a supramolecular complex containing adenosine deaminase acting on RNA (ADAR) family members. We propose a working model in which PCA3 acts as a dominant-negative oncogene in prostate cancer and show consistent results in therapeutic preclinical models and in patient-derived human samples. Therefore, the molecular interaction of PRUNE2...

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Section: Levels Of Pca3 and Prune2 Inversely Correlate In Human Prostmentioning

confidence: 72%

PRUNE2 is a human prostate cancer suppressor regulated by the intronic long noncoding RNA PCA3

Salameh

Lee

Cardó-Vila

et al. 2015

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

236

191

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“…MAP6 is also involved in crosstalk between the actin and MT cytoskeleton networks (Baratier et al, 2006), and between intermediate filaments and MTs, as well as in the dendritic trafficking of lysosomes through its interaction with Bmcc1s (an intermediate-filament-and MT-associated protein involved in the regulation of cytoskeleton dynamics in mouse brain) (Arama et al, 2012). MAP6 also interacts with TMEM106B (a late endosome and lysosomal protein in neurons) (Schwenk et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Human FAM154A (SAXO1) is a microtubule-stabilizing protein specific to cilia and related structures

Dacheux

Roger

Bosc

et al. 2015

Journal of Cell Science

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Cilia and flagella are microtubule-based organelles present at the surface of most cells, ranging from protozoa to vertebrates, in which these structures are implicated in processes from morphogenesis to cell motility. In vertebrate neurons, microtubule-associated MAP6 proteins stabilize cold-resistant microtubules through their Mn and Mc modules, and play a role in synaptic plasticity. Although centrioles, cilia and flagella have cold-stable microtubules, MAP6 proteins have not been identified in these organelles, suggesting that additional proteins support this role in these structures. Here, we characterize human FAM154A (hereafter referred to as hSAXO1) as the first human member of a widely conserved family of MAP6-related proteins specific to centrioles and cilium microtubules. Our data demonstrate that hSAXO1 binds specifically to centriole and cilium microtubules. We identify, in vivo and in vitro, hSAXO1 Mn modules as responsible for microtubule binding and stabilization as well as being necessary for ciliary localization. Finally, overexpression and knockdown studies show that hSAXO1 modulates axoneme length. Taken together, our findings suggest a fine regulation of hSAXO1 localization and important roles in cilium biogenesis and function.

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“…In this non-tumourigenic setting we detected a strong ~80 kDa band in brain tissues, with lower expression of a smaller 72 kDa band (Figure S4). The 52kDa BMCC1s identified by Arama et al [11] was not observed here because the antigen for Ab-4 spans amino acids 2192-2433 of BMCC1-1 and does not contain any portion of BMCC1s (see Figure S2). To confirm expression of BMCC1 in a prostate cancer tumour setting, immunohistological staining of prostate cancer tissues was performed using Ab-3.…”

Section: Resultsmentioning

confidence: 77%

“…Clarke et al [5] demonstrated that BMCC1 RNA expression is elevated in prostate cancer and metastases compared with benign tissue, indicating that BMCC1 may be functioning differently in different cancers and tissue types. An overview of BMCC1 isoform expression and the diverse functions of BCH domain containing proteins is provided in recent publications [10,11]. …”

Section: Introductionmentioning

confidence: 99%

“…More recently, Li et al [12] identified olfaxin proteins corresponding to alternative BMCC1 transcription start sites expressed in the olfactory bulb, with the predominant band at 52 kDa. Arama et al [11] detected a band of the same size in whole brain lysates and cultured neurons and astrocytes, which they called BMCC1s. In the present study, expression and initial characterisation of a single 340 kDa BMCC1 protein in the prostate cancer cell line LNCaP is described.…”

Section: Introductionmentioning

confidence: 99%

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BMCC1 Is an AP-2 Associated Endosomal Protein in Prostate Cancer Cells

et al. 2013

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The prostate cancer antigen gene 3 (PCA3) is embedded in an intron of a second gene BMCC1 (Bcl2-/adenovirus E1B nineteen kDa-interacting protein 2 (BNIP-2) and Cdc42GAP homology BCH motif-containing molecule at the carboxyl terminal region 1) which is also upregulated in prostate cancer. BMCC1 was initially annotated as two genes (C9orf65/PRUNE and BNIPXL) on either side of PCA3 but our data suggest that it represents a single gene coding for a high molecular weight protein. Here we demonstrate for the first time the expression of a >300 kDa BMCC1 protein (BMCC1-1) in prostate cancer and melanoma cell lines. This protein was found exclusively in the microsomal fraction and localised to cytoplasmic vesicles. We also observed expression of BMCC1 protein in prostate cancer sections using immunohistology. GST pull down, immunoprecipitation and mass spectrometry protein interaction studies identified multiple members of the Adaptor Related Complex 2 (AP-2) as BMCC1 interactors. Consistent with a role for BMCC1 as an AP-2 interacting endosomal protein, BMCC1 co-localised with β-adaptin at the perinuclear region of the cell. BMCC1 also showed partial co-localisation with the early endosome small GTP-ase Rab-5 as well as strong co-localisation with internalised pulse-chase labelled transferrin (Tf), providing evidence that BMCC1 is localised to functional endocytic vesicles. BMCC1 knockdown did not affect Tf uptake and AP-2 knockdown did not disperse BMCC1 vesicular distribution, excluding an essential role for BMCC1 in canonical AP-2 mediated endocytic uptake. Instead, we posit a novel role for BMCC1 in post-endocytic trafficking. This study provides fundamental characterisation of the BMCC1 complex in prostate cancer cells and for the first time implicates it in vesicle trafficking.

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Bmcc1s, a Novel Brain-Isoform of Bmcc1, Affects Cell Morphology by Regulating MAP6/STOP Functions

Cited by 16 publications

References 36 publications

PRUNE2 is a human prostate cancer suppressor regulated by the intronic long noncoding RNA PCA3

PRUNE2 is a human prostate cancer suppressor regulated by the intronic long noncoding RNA PCA3

Human FAM154A (SAXO1) is a microtubule-stabilizing protein specific to cilia and related structures

BMCC1 Is an AP-2 Associated Endosomal Protein in Prostate Cancer Cells

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