Parcs/Gpn3 is required for the nuclear accumulation of RNA polymerase II

Calera, Mónica R.; Zamora-Ramos, Cristina; Araiza-Villanueva, Minerva Georgina; Moreno-Aguilar, Carlos; Peña-Gómez, Sonia G.; Castellanos-Terán, Fabiola; Robledo-Rivera, Angélica Y.; Sánchez‐Olea, Roberto

doi:10.1016/j.bbamcr.2011.07.005

Cited by 28 publications

(54 citation statements)

References 28 publications

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“…7B) cells, by immunohistochemical analysis. As previously reported for various types of tissues and tumors [36], most of the POLR2A staining was located in the nucleus in these tumors (Fig. 6D, 7A, 7B).…”

Section: Resultssupporting

confidence: 87%

Nuclear Localization of CD26 Induced by a Humanized Monoclonal Antibody Inhibits Tumor Cell Growth by Modulating of POLR2A Transcription

et al. 2013

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CD26 is a type II glycoprotein known as dipeptidyl peptidase IV and has been identified as one of the cell surface markers associated with various types of cancers and a subset of cancer stem cells. Recent studies have suggested that CD26 expression is involved in tumor growth, tumor invasion, and metastasis. The CD26 is shown in an extensive intracellular distribution, ranging from the cell surface to the nucleus. We have previously showed that the humanized anti-CD26 monoclonal antibody (mAb), YS110, exhibits inhibitory effects on various cancers. However, functions of CD26 on cancer cells and molecular mechanisms of impaired tumor growth by YS110 treatment are not well understood. In this study, we demonstrated that the treatment with YS110 induced nuclear translocation of both cell-surface CD26 and YS110 in cancer cells and xenografted tumor. It was shown that the CD26 and YS110 were co-localized in nucleus by immunoelectron microscopic analysis. In response to YS110 treatment, CD26 was translocated into the nucleus via caveolin-dependent endocytosis. It was revealed that the nuclear CD26 interacted with a genomic flanking region of the gene for POLR2A, a subunit of RNA polymerase II, using a chromatin immunoprecipitation assay. This interaction with nuclear CD26 and POLR2A gene consequently led to transcriptional repression of the POLR2A gene, resulting in retarded cell proliferation of cancer cells. Furthermore, the impaired nuclear transport of CD26 by treatment with an endocytosis inhibitor or expressions of deletion mutants of CD26 reversed the POLR2A repression induced by YS110 treatment. These findings reveal that the nuclear CD26 functions in the regulation of gene expression and tumor growth, and provide a novel mechanism of mAb-therapy related to inducible translocation of cell-surface target molecule into the nucleus.

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Section: Resultssupporting

confidence: 87%

Nuclear Localization of CD26 Induced by a Humanized Monoclonal Antibody Inhibits Tumor Cell Growth by Modulating of POLR2A Transcription

et al. 2013

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“…15, 17, 23, 27 and 28) and transcription regulators 29 . Later, studies refined this activity and demonstrated that GPN1 and GPN3 were essential to RNAPII nuclear import 17 , 27 , 30 . Actually, with the formations gathered on the GPN-GTPases, it appears currently difficult to establish a correlation between the association of GPN-GTPases with RNA polymerase II and GPN-GTPases function in sister chromatid cohesion mechanism.…”

Section: Discussionmentioning

confidence: 99%

Eukaryotic GPN-loop GTPases paralogs use a dimeric assembly reminiscent of archeal GPN

et al. 2013

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GTPases are molecular switches that regulate a wide-range of cellular processes. The GPN-loop GTPase (GPN) is a sub-family of P-loop NTPase that evolved from a single gene copy in archaea to triplicate paralog genes in eukaryotes, each having a non-redundant essential function in cell. In Saccharomyces cerevisiae, yGPN1 and yGPN2 are involved in sister chromatid cohesion mechanism, whereas nothing is known regarding yGPN3 function. Previous high-throughput experiments suggested that GPN paralogs interaction may occur. In this work, GPN|GPN contact was analyzed in details using TAP-Tag approach, yeast two-hybrid assay, in silico energy computation and site-directed mutagenesis of a conserved Glu residue located at the center of the interaction interface. It is demonstrated that this residue is essential for cell viability. A chromatid cohesion assay revealed that, like yGPN1 and yGPN2, yGPN3 also plays a role in sister chromatid cohesion. These results suggest that all three GPN proteins act at the molecular level in sister chromatid cohesion mechanism as a GPN|GPN complex reminiscent of the homodimeric structure of PAB0955, an archaeal member of GPN-loop GTPase.

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“…Interactions of the GPN proteins with RNAPII have been documented in two other recent studies (2,6). Interestingly, GPN proteins have also been demonstrated to interact with the CCT complex, which controls the polymerization of tubulins into microtubules (9).…”

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confidence: 97%

Regulating the Shuttling of Eukaryotic RNA Polymerase II

Croce

2011

Molecular and Cellular Biology

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The eukaryotic RNA polymerase II (RNAPII) transcribes most protein-coding RNAs (mRNAs) and the capped noncoding RNAs (ncRNAs), including microRNAs (miRNAs), small nuclear RNAs (snRNAs), and small nucleolar RNAs (snoRNAs) (10). In the past 3 decades, our knowledge about the functional role of RNAPII during gene transcription has dramatically advanced (8). However, there are still several open questions regarding the regulatory mechanisms involved in the steps before and after transcription. In particular, how RNAPII is imported into the nucleus remains elusive. In this issue, Carré and Shiekhattar (3) report that the evolutionarily conserved GTPases GPN1 and GPN3 stably associate with and regulate the nuclear import of the human RNAPII. These exciting results now make it possible to begin to dissect the regulatory pathways of the intracellular localization and nuclear import of RNAPII.Recently, the structures and subunit compositions of the three RNA polymerases (Table 1) have been characterized (4). RNAPII is a highly conserved enzyme composed of 12 subunits, 10 of which form the central core. The other two subunits (Rpb4 and Rpb7) form a peripheral heterodimer that protrudes out from the core enzyme structure. This stabilizes the RNAPII complex in clamp-closed conformation, favoring efficient transcription initiation. Rpb10 and Rpb12 are common subunits for all of the eukaryotic RNA polymerases and are implicated in the interaction with the basal transcription factors, such as the TATA box-binding protein (TBP). These interactions lead to the formation of the preinitiation complex (PIC), which contains RNAPII as well as the general transcription factors TFIIA, TFIIB, TFIID, TFIIE, TFIIF, and TFIIH. In the past years, numerous coactivators that both facilitate the access of PIC to its target promoters and increase the stability of the complex have been functionally characterized. Recent data (1) indicate that the RNAPII assembly pathway occurs in the cytoplasm and that assembly is coordinated by the consecutive actions of the cochaperone hSpagh and the chaperone Hsp90. The two largest subunits, Rpb1 and Rpb2, are initially preassembled into two separated subcomplexes, together with several other subunits that are either common to all three RNA polymerases or are specific for RNAPII (Fig. 1). It is likely that the two subcomplexes are then assembled together before they enter the nucleus through the nuclear pore complex (NPC). Interestingly, it now seems that access to the nucleus is restricted exclusively to the assembled RNAPII, thus preventing any premature binding of the independent subunits at promoter regions.But the question of how the assembled RNAPII is imported into the nucleus remains. How is this step regulated? Carré and Shiekhattar tackled this question using a combination of cell biology approaches and mass spectrometry of affinity-purified complexes containing tagged cytoplasmic and nuclear RNAPII (3). They identified GPN1 and GPN3 as novel interactors of the RNAPII, which remained associated with...

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Parcs/Gpn3 is required for the nuclear accumulation of RNA polymerase II

Cited by 28 publications

References 28 publications

Nuclear Localization of CD26 Induced by a Humanized Monoclonal Antibody Inhibits Tumor Cell Growth by Modulating of POLR2A Transcription

Nuclear Localization of CD26 Induced by a Humanized Monoclonal Antibody Inhibits Tumor Cell Growth by Modulating of POLR2A Transcription

Eukaryotic GPN-loop GTPases paralogs use a dimeric assembly reminiscent of archeal GPN

Regulating the Shuttling of Eukaryotic RNA Polymerase II

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