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RAN (RAN, member RAS oncogene family)

Written2009-11Wilhelmina Maria Rensen, Patrizia Lavia
Institute of Molecular Biology, Pathology, CNR (National Research Council), c/o Sapienza University of Rome, via degli Apuli 4, 00185 Rome, Italy

(Note : for Links provided by Atlas : click)

Identity

LocusID (NCBI) 5901
Atlas_Id 42039
Location 12q24.33  [Link to chromosome band 12q24]
Location_base_pair Starts at and ends at bp from pter
Fusion genes
(updated 2016)
GSTM2 (1p13.3) / RAN (12q24.33)LOC100507412 (-) / RAN (12q24.33)RAN (12q24.33) / CD74 (5q32)

DNA/RNA

 
Description The gene encompasses 4,80 Kb of DNA; 7 exons.
Transcription 1657 bp mRNA; 651 bp CDS.

Protein

Description 216 amino acids; originally identified for harbouring a GTP nucleotide-binding domain sharing homology to that of Ras.
Expression RAN was originally cloned as a differentially expressed cDNA in a human teratocarcinoma cell line (NTera2) and was found to be downregulated in NTera2 cells induced to differentiate (Drivas et al., 1990). The RAN protein is generally highly expressed in actively proliferating and transformed cells (Azuma et al., 2004; Xia et al., 2008; Rensen et al., 2008; www.oncomine.org).
Localisation RAN is a shuttling GTPase protein that moves between the nucleus and the cytoplasm in interphase. A fraction of RAN also accumulates at the nuclear envelope. As all other GTPases, RAN is subjected to cycles of GTP exchange and subsequent hydrolysis to GDP. The subcellular localisation of RAN is mainly dependent on the guanine nucleotide that binds to it. In the nucleus, RAN is in the GTP-bound form, because the nucleus contains the guanine exchange factor for RAN, RCC1, a chromatin-binding protein that generates RANGTP (Bischoff and Ponstingl, 1991). On the contrary, cytoplasmic RAN is GDP-bound, because the cytoplasm contains two abundant hydrolysis factors, RANGAP1 (Bischoff et al., 1994) and RANBP1 (Bischoff et al., 1995), which cooperate to hydrolyse GTP on RAN, thus generating RANGDP. Therefore, nucleotide turnover on RAN is associated with a complete shuttling cycle, i.e. RAN nuclear entry (to be GTP-loaded) and subsequent translocation to the cytoplasm (to be hydrolysed to RANGDP) (Smith et al., 2002).
In mitosis, the RCC1 exchange factor remains largely chromosome-associated and continues to generate RANGTP. Given that the nuclear envelope has dissolved by this point, this determines a high RANGTP concentration near mitotic chromosomes, where RCC1 is anchored, gradually diluting towards the cell periphery. Some authors have defined this pattern the 'chromatin-centered gradient diffusion model' (Caudron et al., 2005; Kaláb et al., 2006; Li et al., 2007). Highly mobile RANGTP generated at chromosomes, however, does not simply diffuse freely. Fractions of RANGTP can in fact associate with specific effectors at various sites in the mitotic apparatus (e.g. centrosomes, spindle poles and spindle microtubules); the local accumulation of RANGTP at these sites regulates a variety of downstream mitotic factors therein (Quimby and Dasso, 2003; Ciciarello et al., 2007; Clarke and Zhang, 2008).
Function Nucleocytoplasmic transport of proteins and RNAs
The ability of the RAN GTPase to shuttle between the nucleus and the cytoplasm parallels its function as a regulator of nucleo-cytoplasmic transport of RNAs and proteins in interphase cells (Izaurralde et al., 1997). This is a highly conserved process from lower eukaryotes to humans. A wealth of studies over more than years have elucidated structural, biochemical and cellular aspects of the process, which cannot be summarised here but are discussed in many reviews (e.g. Mattaj and Englmeier, 1998; Görlich and Kutay, 1999; Clarke and Zhang, 2001; Macara, 2001; Kuersten et al., 2001; Weis, 2003; Pemberton and Paschal, 2005). The role of RAN in the process can be tentatively schematised as follows.
- GDP-bound RAN enters the nucleus associated with a specific transport factor, NTF2 (nuclear transport factor 2). In the nucleus, the RCC1 guanine exchange factor exchanges GDP with GTP on RAN; this generates RANGTP.
- In the nucleus, RANGTP can bind several effectors that contain RAN-binding domains. An important group of RAN nuclear effectors makes up the importin beta superfamily of nuclear transport receptors, which includes exportin/CRM1, importin beta and others.
- Among RANGTP effectors, importin beta is the universal vector of protein import in nuclei and forms import complexes with various cargo proteins. The latter are often, but not obligatorily, characterised by nuclear localisation signal, NLS (short stretches of negatively charged aminoacids). Nuclear cargoes may bind importin beta directly or through a member of the importin alpha proteins, which can act as 'adaptor' molecules for NLSs with subtle sequence preference. Importin beta drives the import complex from the cytoplasm to the nucleus through nuclear pores.
- Upon entry of the import complex in nuclei, RCC1-generated RANGTP binds importin beta. This interaction disassembles the import complex and triggers the release of free cargo proteins in the nucleus. RANGTP therefore acts as an essential regulator in termination of protein import in nuclei and it is absolutely required for the release of nuclear proteins in a free, biologically productive state.
- Export vectors (CRM1, exportin-5 and others) also contain RAN-binding domains with which RANGTP can interact. Export vectors in the nucleus associate with distinct classes of RNAs or with proteins that have to be exported to the cytoplasm. For example, exportin-5 is specific for microRNAs that, after processing from double-stranded RNA precursors, are exported to the cytoplasm in order to regulate gene expression post-transcriptionally. CRM1 is the export vector for many shuttling proteins, e.g. p53, which perform distinct functions in the nucleus and in the cytoplasm; proteins to be exported via CRM1 are characterised by nuclear export signals (NES), short stretches of hydrophobic residues. All export complexes, whether RNA-based or protein-based, require RANGTP for their stabilisation. In other words, the exportin(s) recognise their specific cargos but the assembly of a functional export complex requires RANGTP association and formation of a trimeric RANGTP/exportin/cargo complex. Nuclear RANGTP is therefore a limiting factor in the process of nuclear export.
- The concentration of RANGTP in the nucleus is therefore essential for nucleo-cytoplasmic transport of macromolecules across the nuclear envelope, and ultimately for their proper localisation in the subcellular compartment in which they will function.
- After disassembly of the import complexes in the nucleus, and release of cargoes in the nucleoplasm, RANGTP can exit the nucleus in complex with its effector importin beta.
- The cytoplasm contains the hydrolysis factor RANGAP1 and its co-activator RANBP1, which together cooperate to hydrolyse GTP to GDP on RAN. Cytoplasmic RAN therefore returns GDP-bound and is ready to associate with NTF2 and initiate a novel transport cycle.

Mitotic spindle regulation
In mitosis the nuclear envelope breaks down and the nucleus and cytoplasmic compartments merge. At this stage, RAN takes on a second role as a global regulator of the mitotic apparatus. A large number of studies describe mitotic phenotypes associated with an imbalance in the RAN cycle, indicating that multiple steps of the mitotic division are under RAN control. Here it would not be possible to summarise all relevant studies, but many reviews address possible mechanisms of RAN in mitotic control and converge in identifying RAN as a master regulator of mitosis (Clarke and Zhang, 2008; Kalab and Heald, 2008; Ciciarello et al., 2007; Arnaoutov and Dasso, 2005; Di Fiore et al., 2004; Weis, 2003; Hetzer et al., 2002; Moore, 2001). Relevant aspects are highlighted below.
- Centrosome function. A fraction of RAN localizes at centrosomes through the anchoring protein AKAP450, a large coil-coiled scaffolding protein that tethers several factors to the centrosomes; RAN displacement from centrosomes, induced by expressing a dominant negative mutant of the anchoring protein AKAP450, prevents the formation of centrosomal microtubule asters (Keryer et al., 2003). RAN is also indirectly involved in control of centrosome duplication because it cooperates with CRM1 in regulating the centrosomal recruitment of the centrosome duplication 'licensing' factor nucleophosmin (NPM) (Wang et al., 2005). Interestingly, some viral proteins that cause abnormal centrosome organisation and/or duplication, e.g. HLTV-1 Tax (Peloponese et al., 2005) and HPV E7 (De Luca et al., 2003), interact with the centrosomal RAN fraction and disrupt the centrosomal regulatory functions of RAN (Lavia et al., 2003).
- Mitotic spindle assembly and function. RAN is indispensable for the organisation and dynamic functions of microtubules in the mitotic spindle (Ohba et al., 1999; Carazo-Salas et al., 1999; Wilde and Zheng, 1999; Kalab et al., 1999; Zhang et al., 2009). RAN regulates the organisation of mitotic microtubules, both from centrosomes, in what is regarded as the most classical microtubule nucleation pathway, and from kinetochores (Tulu et al., 2006; Torosantucci et al., 2008; O'Connell et al., 2009); the latter is regarded as an alternative pathway that is activated when the centrosomal activity is impaired, for example by mutation in centrosomal factors, or when microtubule nucleation is reactivated after treatment with microtubule-targeting drugs (O'Connell and Khodjakov, 2007). A variety of mitotic factors are targets of RAN control and mediate the spindle-organising role of RAN (Clarke and Zhang, 2008; Kalab and Heald, 2008; Ciciarello et al., 2007). Mutations, or silencing, of regulators of the nucleotide-bound state of RAN imbalance the RAN cycle and result in a variety of mitotic abnormalities; recurrent elements include: a) the failure to establish a bipolar spindle, with the formation of multipolar spindles that drive unequal chromosome segregation to more than one pole; b) chromosome misalignment at the cell equator; c) altered microtubule dynamics, eventually resulting in chromosome segregation errors. All of these conditions ultimately contribute to the loss of fidelity in chromosome segregation.
- Microtubule/kinetochore interactions and spindle checkpoint function (Arnaoutov and Dasso, 2005). Imbalance in the RAN cycle is associated with abnormal attachments between microtubules and the kinetochores of chromosomes, with an ensuing failure of chromosome biorientation; cells carrying such imbalance often progress to segregate chromosomes in the presence of incomplete or incorrect microtubule attachments to kinetochores, suggesting that the microtubule defects go undetected by the mitotic spindle checkpoint. RAN mechanisms in the process are not fully understood, but it has been observed that the nucleoporin RANBP2/NUP358, a RAN-binding protein that is endowed with E3 SUMO ligase activity, as well as RANGAP1, the hydrolysis factor for RAN, which is a substrate of SUMOylation by RANBP2/NUP358, must both be recruited at kinetochores in a RANGTP-dependent manner in order to control the spindle checkpoint schedule in response to microtubule attachments to kinetochores (Joseph et al., 2002; Joseph et al., 2004; Salina et al., 2003; Arnaoutov et al., 2005; Zuccolo et al., 2007).

Nuclear envelope organisation and nuclear pore assembly
When mitosis terminates, RAN has roles in the organisation of the nuclear envelope and nuclear pores in the reforming interphase nucleus. The requirement for RAN in the process is indicated by experiments with in vitro cell-free reconstitution systems, as well as in genetic experiments in yeast and in C.elegans in vivo (reviewed by Clarke and Zhang, 2001; Hetzer et al., 2002). Some of these experiments, in particular with yeast mutants, also indicates a requirement for RAN activity in initiation of nuclear pore formation, without which the nuclear envelope precursors would fuse in a sealed envelope incapable of supporting nucleo-cytoplasmic transport. In human cells, some RAN enrichment is seen at the nuclear envelope with a punctuate pattern coinciding with nuclear pores; this reflects the accumulation of a fraction of RAN therein, possibly through interactions with the nucleoporin RANBP2/NUP358, which contains four Ran-binding domains.

Apoptosis
A role of RAN in regulating the apoptotic response to a variety of stimuli is increasingly being recognized (Woo et al., 2008; Tietze et al., 2008; Wong et al., 2009). RAN function in apoptosis is just emerging and is therefore incompletely understood as yet. Available studies implicate RAN in at least two major apoptotic pathways.
- The first pathway, triggered by DNA damage, involves the delocalisation of RAN network members from the nucleus and entails a key role of RCC1 as a 'sensor' of apoptotic modification in chromatin; one downstream factor that the RAN system targts in this response is NF-kB (Wong et al., 2009).
- The second pathway is triggered by microtubule-emanating signals. RAN network members have roles in microtubule dynamics and interplay with many factors that can increase, or decrease, mitotic microtubule stability, hence inducing abnormal mitotic delay. RAN and its regulators can trigger the apoptotic response via microtubules and can modulate apoptosis induction by microtubule-targeting chemotherapeutic agents. The underlying molecular pathway seems to be independent on p53 but dependent on caspases (Woo et al., 2008; Rensen et al., 2009).

Summary
RAN regulates:
- the subcellular localisation of nuclear and cytoplasmic macromolecules in interphase,
- the organisation and function of the mitotic apparatus after nuclear envelope breakdown, and
- the reorganisation of the nuclear envelope after mitosis,
- the apoptotic response to a variety of conditions.
RAN roles in these basic processes underlie the requirement for RAN function for cell viability and duplication and account for the abnormal proliferation and genetic instability observed in cells with RAN deregulated activity.

To be noted
In addition to 'classical' RAN-dependent functions described above, a recent work highlights a novel interactions of RAN with RASSF1, a tumor suppressor protein sharing similarities with RAS effector proteins (Dallol et al., 2009). RASSF1 regulates apoptosis and loss of RASSF1 is common in a variety of human cancers.

Homology GTP-binding domain of members of the Ras superfamily of GTPases.

Mutations

Note No spontaneous mutations are reported to occur in human cells. Mutant versions of human RAN have been synthesized which either mimic the GDP-bound conformation (substitution mutant T24N) or are resistant to hydrolysis and remain stably GTP-bound (substitution mutants Q69L G19V L43E) or are impaired in association with interacting partners (deletion mutant delta DE).

Implicated in

Note
Note Abnormal RAN activity is increasingly proving to be implicated in cancer. In addition to cancer profiling studies available through the oncomine database (Oncomine 4 Research Edition, www.oncomine.org), many in-depth cancer studies implicate RAN in human cancer types (only studies of human cancers are reported below).
  
Entity Cervical cancer
Oncogenesis Gain of 12q13.12-q24.2 was detected in Affymetrix arrays and RAN was found to be overexpressed in this region of 12q. In particular, RAN was overexpressed in cervical intraepithelial neoplasia (CIN) and invasive cervical cancers. RAN can physically interact with HPV-derived E7 oncogene; this interaction is associated with the appearance of supernumerary centrosomes and abnormal mitotic spindles that can generate aneuploid cells. This can increase the malignancy of HPV-associated cervical cancers. (Fitzpatrick et al., 2006; De Luca et al., 2003).
  
Entity Prostate cancer
Oncogenesis increased expression of RAN is detected in a large proportion of primary prostate cancers with different degrees of differentiation, preferentially in epithelial cells. RAN has been independently re-identified as ARA24, a co-activator of the androgen receptor (AR). RAN interacts physically with the androgen receptor (AR) and increases AR transactivation. The AR pathway is of fundamental importance for growth and progression of prostate adenocarcinoma. (Li et al., 2002; Hsiao et al., 1999; Harada et al., 2008).
  
Entity Ovarian cancer
Prognosis RAN is a specific and sensitive marker to define the patient outcome: high levels of RAN appear to be tightly associated with a poor prognosis (p<0.001).
Oncogenesis In serous epithelial ovarian cancer cells, RAN abundance is statistically significantly higher in tumors of Grade 1 (p=0.003), Grade 2 and Grade 3 (both p<0.001) compared to G0 (low malignant potential) and in advanced (p=0.001) compared to early stage tumors. RAN and CCNE1 (cyclin E1) are the most specific markers to define the tumor invasiveness. (Oullet et al., 2006).
  
Entity Breast cancer
Oncogenesis Overexpression of RAN is associated with malignancy in human breast cancer cell lines. RAN may potentially function in osteopontin (OPN)-induced invasion and metastasis of breast cancer cell lines. (Kurisetty et al., 2008; Kurisetty et al., 2009).
  
Entity Colon cancer
Oncogenesis Three independent studies demonstrated that RAN is upregulated in colon tumors compared to normal colon tissues. (Bertucci et al., 2004; Lin et al., 2002; Hung et al., 2009).
  
Entity Renal cancer
Prognosis Overexpression of RAN is associated with poorly differentiated grade, local invasion, metastases and unfavorable prognosis in renal cancer.
Oncogenesis RAN protein levels are significantly upregulated in renal tumors compared to non tumor samples. (Abe et al., 2008).
  
Entity Mesothelioma
Oncogenesis RAN is upregulated in malignant pleural mesothelioma compared to parietal pleura. (Røe et al., 2009).
  
Entity Nasopharyngeal cancer
Oncogenesis RAN was significantly overexpressed in more than 80% of nasopharyngeal carcinoma tissues compared to normal nasopharynx tissues. (Li et al., 2006).
  
Entity Glioblastoma
Oncogenesis RAN was identified as a suppressor of the pro-apoptotic regulator Bax, a member of the Bcl-2 family of proteins, in a U373MG human glioblastoma-derived cDNA library. RAN overexpression resulted in a decrease of paclitaxel-induced apoptosis and was hypothesized to act via downregulation of JNK-dependent signalling pathways in this glioblastoma cell line. (Woo et al., 2008).
  
Entity Lymphoma
Prognosis High levels of RAN, MYC, POLE2 and SLC29A2 were associated with poor survival in patients with mantle-cell lymphoma. This can be used as a molecular diagnostic test. (Hartmann et al., 2008).
  
Entity Myeloma
Prognosis In myeloma patients RAN overexpression is associated with rapid relapse. (Harousseau et al., 2004).
  
Entity T-cell leukemia
Oncogenesis RAN interacts with the Tax protein of the oncogenic retrovirus Human T cell leukemia virus type-1 (HTLV-1), which is the etiological agent of adult T-cell leukemia. This interaction is associated with the appearance of supernumerary centrosomes and abnormal mitotic spindles that can generate aneuploid cells. (Peloponese et al., 2005).
  
Entity Various cancers and cancer cell lines
Oncogenesis RAN is upregulated in various cancer cell lines (colon adenocarcinoma HCT116, SW620 and COLO 201; breast adenocarcinoma MCF-7 and MDA-MB-231; B lymphoblastoid Raji; lung adenocarcinoma H460, H1975 and LC-1; lung squamous cell carcinoma QG-56; epithelial carcinoma A431; prostate adenocarcinoma PC3; gastric adenocarcinoma MKN-28, MKN-45, SSTW-9, KATO-III, KWS and HGC-27; head and neck carcinoma KUMA-1; pancreatic adenocarcinoma Panc-1; human chronic myelogenous leukemia K5629), tumor samples (human renal cell carcinoma, ovarian adenocarcinoma, soft tissue sarcoma), and tumor-infiltrating lymphocytes from scirrhous-type gastric adenocarcinoma. (Azuma et al., 2004; Xia et al., 2008).
  

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Citation

This paper should be referenced as such :
Rensen, WM ; Lavia, P
RAN (RAN, member RAS oncogene family)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(9):834-840.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/RANID4203912q24.html


Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  t(7;9)(q11;p12) PAX5/POM121


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