BNIP2 extra long inhibits RhoA and cellular transformation by Lbc RhoGEF via its BCH domain

Soh, Unice J. K.; Low, Boon Chuan

doi:10.1242/jcs.021774

Cited by 38 publications

(64 citation statements)

References 55 publications

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“…S9A). BCH inhibits RhoA, a small GTPase that regulates the cytoskeleton, cell adhesion, and migration (16), whereas DHHA2 interacts with Nm23-H1, a metastasis suppressor (17). We found that endogenous PRUNE2 coimmunoprecipitates with RhoA and Nm23-H1 (Fig.…”

Section: Pca3mentioning

confidence: 64%

“…S10 E-J). These results, along with the established functions of interacting proteins (16)(17)(18), suggest that PRUNE2 primarily decreases tumor growth by inhibiting cell proliferation but also affects adhesion, spreading, and migration. We subsequently extended these results to human tumor xenograft models; LNCaP prostate cancer cells stably expressing PRUNE2-shRNA, ectopic PCA3, PCA3-shRNA, or controls were s.c. administered into SCID mice.…”

Section: Pca3mentioning

confidence: 78%

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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.

230

185

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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: Pca3mentioning

confidence: 64%

Section: Pca3mentioning

confidence: 78%

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.

230

185

View full text Add to dashboard Cite

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“…On the other hand, BMCC1 was reported to be preferentially expressed in favorable neuroblastoma (Machida et al 2006). More recently, it was shown that a BNIP2 and cdc42GAP homology (BCH) domain of BMCC1 suppresses the transformation of cultured cells initiated by Lbc, a RhoA-specific guanine nucleotide exchange factor (RhoGEF), via binding to Rho family proteins (Soh and Low 2008). In the present study, we isolated complementary DNA (cDNA) clones for the full-length PRUNE2 protein and demonstrated the expression of endogenous full-length PRUNE2 protein.…”

Section: Introductionmentioning

confidence: 74%

“…Soh et al reported that BNIPXL, which corresponds to the C-terminal region of PRUNE2, interacts with RhoA and RhoC (Soh and Low 2008). Therefore, it is likely that PRUNE2 protein, which is associated with the Rho family small G proteins and may indirectly bind to 8-oxo-GTP/GTP-immobilized-Sepharose, was detected in the nucleotide-bound fractions.…”

Section: Discussionmentioning

confidence: 99%

“…From KNS81 cells, we identified 20 candidates for PRUNE2-associating proteins by co-immunoprecipitation. Among them, T-cell activation Rho GTPase-activating protein, TAGAP, is one of the most interesting molecules because the C-terminus of PRUNE2 was previously reported to inactivate Rho family small G protein by inhibiting a RhoGEF, Lbc (Soh and Low 2008). As TAGAP possesses a Rho-GAP domain (Mao et al 2004), PRUNE2 might regulate the activity of Rho family small G proteins by controlling the function of TAGAP in addition to Lbc.…”

Section: Discussionmentioning

confidence: 99%

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Cancer-Related PRUNE2 Protein Is Associated with Nucleotides and Is Highly Expressed in Mature Nerve Tissues

et al. 2011

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Human PRUNE is thought to enhance the metastasis of tumor cells. We found that a hypothetical paralog of PRUNE, PRUNE2, binds to 8-oxo-GTP, an oxidized form of GTP. Hypothetical PRUNE2 gene consists of C9orf65 and BMCC1/BNIPXL, both of which are malignant tumor-associated genes. We isolated PRUNE2 complementary DNA and revealed that the protein is composed of 3,062 residues. C9orf65 and BMCC1/BNIPXL encode the N-terminal part (259 residues) and C-terminal part (2,729 residues) of PRUNE2, respectively. We demonstrated the endogenous full-length PRUNE2 protein (338 kDa) by Western blot and mass spectrometry. PRUNE2 bound to 8-oxo-GTP as well as GTP. The expression levels of human PRUNE2 and mouse Prune2 messenger RNA (mRNA) were highest in the dorsal root ganglia (DRG) and, to a lesser extent, in other nerve tissues. DRG neurons express higher levels of PRUNE2 in their soma compared with adjacent cells. In addition, their expression levels in the adult nerve tissues were higher than those in fetal or neonatal nerve tissues. The present study indicates that C9orf65 and BMCC1/BNIPXL are transcribed as PRUNE2 mRNA, which is translated to a large PRUNE2 protein. The nerve tissue-specific and post-development expression of PRUNE2/Prune2 suggests that PRUNE2 may contribute to the maintenance of mature nervous systems.

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BNIP‐2 Activation of Cellular Contractility Inactivates YAP for H9c2 Cardiomyoblast Differentiation

et al. 2022

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RhoGTPases and Hippo kinases are key regulators of cardiomyoblast differentiation. However, how these signaling axes are coordinated spatiotemporally remains unclear. Here, the central and multifaceted roles of the BCH domain containing protein, BNIP-2, in orchestrating the expression of two key cardiac genes (cardiac troponin T [cTnT] and cardiac myosin light chain [Myl2]) in H9c2 and human embryonic stem cell-derived cardiomyocytes are delineated. This study shows that BNIP-2 mRNA and protein expression increase with the onset of cTnT and Myl2 and promote the alignment of H9c2 cardiomyocytes. Mechanistically, BNIP-2 is required for the inactivation of YAP through YAP phosphorylation and its cytosolic retention. Turbo-ID proximity labeling corroborated by super-resolution analyses and biochemical pulldown data reveals a scaffolding role of BNIP-2 for LATS1 to phosphorylate and inactivate YAP in a process that requires BNIP-2 activation of cellular contractility. The findings identify BNIP-2 as a pivotal signaling scaffold that spatiotemporally integrates RhoA/Myosin II and LATS1/YAP mechanotransduction signaling to drive cardiomyoblast differentiation, by switching the genetic programming from YAP-dependent growth to YAP-silenced differentiation. These findings offer insights into the importance of scaffolding proteins in bridging the gap between mechanical and biochemical signals in cell growth and differentiation and the prospects in translational applications.

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BNIP2 extra long inhibits RhoA and cellular transformation by Lbc RhoGEF via its BCH domain

Cited by 38 publications

References 55 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

Cancer-Related PRUNE2 Protein Is Associated with Nucleotides and Is Highly Expressed in Mature Nerve Tissues

BNIP‐2 Activation of Cellular Contractility Inactivates YAP for H9c2 Cardiomyoblast Differentiation

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