Disease relevance of RCC1

• PURPOSE: To describe a macrodeletion spanning entire RCC1-like doman in the RPGR gene in one Japanese family with X-linked retinitis pigmentosa (XLRP) [1].
• Distinctive cell cycle regulatory protein profiles by adenovirus delivery of p53 in human papillomavirus-associated cancer cells [2].
• Replication of herpes simplex virus type 1 DNA is inhibited in a temperature-sensitive mutant of BHK-21 cells lacking RCC1 (regulator of chromosome condensation) and virus DNA remains linear [3].
• Production of mRNAs of HSV-1 early genes required for HSV-1 DNA replication was decreased in tsBN2 at 39.5 degrees C. Therefore, RCC1 was assumed to be involved in the formation of an HSV-1 DNA configuration suitable for replication (that is circularization) and the supply of proteins required for replication of the circularized HSV-1 DNAs [3].
• Cell cycle regulatory gene abnormalities are important determinants of leukemogenesis and disease biology in adult acute lymphoblastic leukemia [4].

High impact information on RCC1

• Structural basis for guanine nucleotide exchange on Ran by the regulator of chromosome condensation (RCC1) [5].
• The predicted 90 kD protein contains in its N-terminal half a tandem repeat structure highly similar to RCC1 (regulator of chromosome condensation), suggesting an interaction with a small GTPase [6].
• We propose that RCC1 generates a high local concentration of Ran-GTP around chromatin which in turn induces the local nucleation of microtubules [7].
• One known regulator, the protein RCC1 (refs 12, 13), interacts with Ran to catalyse guanine nucleotide exchange, and both RCC1 and Ran are components of an intrinsic checkpoint control that prevents the premature initiation of mitosis [8].
• Characterization of proteins that interact with the cell-cycle regulatory protein Ran/TC4 [8].

Chemical compound and disease context of RCC1

• A novel retinoid-related molecule inhibits pancreatic cancer cell proliferation by a retinoid receptor independent mechanism via suppression of cell cycle regulatory protein function and induction of caspase-associated apoptosis [9].
• In tamoxifen-sensitive breast cancer cells, tamoxifen inhibits, whereas estrogen induces, expression of cyclin D1, a key cell cycle regulatory protein [10].
• Retinoic acid is a known morphogen which can regulate cell proliferation and differentiation and also induces the hypophosphorylation of the RB (retinoblastoma tumor suppressor gene) protein, a known cell cycle regulatory protein [11].
• Roscovitine regulates invasive breast cancer cell (MDA-MB231) proliferation and survival through cell cycle regulatory protein cdk5 [12].

Biological context of RCC1

• We have recently isolated a protein from HeLa cells that strongly binds an anti-RCC1 antibody and has the same molecular mass, DNA-binding properties, and amino-acid sequence as the 205 residues already identified [13].
• We propose that the docking of RCC1 to H2A/H2B establishes the polarity of the Ran-GTP gradient that drives nuclear envelope assembly, nuclear transport, and other nuclear events [14].
• Isolation and characterization of the active cDNA of the human cell cycle gene (RCC1) involved in the regulation of onset of chromosome condensation [15].
• Phosphorylation of RCC1 in mitosis is essential for producing a high RanGTP concentration on chromosomes and for spindle assembly in mammalian cells [16].
• This human RCC1 gene was located to human chromosome 1 using sorted chromosomal fractions [15].

Anatomical context of RCC1

• The product of the gene RCC1 (regulator of chromosome condensation) in a BHK cell line is involved in the control of mitotic events [13].
• HeLa cell RCC1 is complexed to a protein of Mr 25K [13].
• Thus, RCC1 protein locates on the chromatin and is not a component of the nuclear matrix [17].
• Surprisingly, we found that neither Xenopus ovarian cytosol nor a mixture of recombinant import factors (karyopherin alpha2, karyopherin beta1, Ran, and p10/NTF2) were able to support the import of pA-RCC1 into the nuclei of digitonin-permeabilized cells [18].
• The steepness of the RanGTP gradient appears limited by both the cytoplasmic RanGAP concentration and the imperfect retention of nuclear RanGTP by nuclear pore complexes (NPCs), but not by the nucleotide exchange activity of RCC1 [19].

Associations of RCC1 with chemical compounds

• The RCC1 protein, a regulator for the onset of chromosome condensation locates in the nucleus and binds to DNA [17].
• Crystals of human RCC1 suitable for X-ray analysis have been obtained using the seeding technique in hanging drops with sodium citrate as a precipitant [20].
• This homozygous G669A mutation in exon 4 is predicted to result in a tyrosine substitution at cysteine 156 of the RCC1 (regulator of chromatin condensation)-like domain, encoding a putative guanine exchange factor for Ran guanosine triphosphatase, leading to a loss of ALS2 function due to instability of mutant protein [21].
• Leptomycin B, which inhibits Crm1/RanGTP-dependent nuclear export, significantly increased the mobility of RCC1 as did high levels of actinomycin D (to inhibit RNA polymerases I, II, and III) or alpha-amanitin (to inhibit RNA polymerases II and III) as well as energy depletion [22].
• Further sudies on the role of the RCC1-like domain in the visual Cascade and additional findings of related proteins in the retina or even other organs, will give us a more precise understanding of this protein [23].

Physical interactions of RCC1

• This interaction was stimulated by the addition of Ran; moreover, Ran.GDP, Ran.GTP, and Ran without nucleotide could all stimulate complex formation between RanBP3 and RCC1 even though binding of Ran.GDP to RanBP3 alone was undetectable [24].
• We find that RCC1 binds directly to mononucleosomes and to histones H2A and H2B [14].
• The C terminus of the nuclear RAN/TC4 GTPase stabilizes the GDP-bound state and mediates interactions with RCC1, RAN-GAP, and HTF9A/RANBP1 [25].
• RRAG A (Rag A)/Gtr1p is a member of the Ras-like small G protein family that genetically interacts with RCC1, a guanine nucleotide exchange factor for RanGTPase [26].

Regulatory relationships of RCC1

• These findings indicate that RanBP1 negatively regulates RCC1 [27].
• Inactivation of the Ran guanine nucleotide exchange factor RCC1 inhibited Smad3 export and led to nuclear accumulation of phosphorylated Smad3 [28].
• Expression of tumor suppressor p53 and the cell cycle regulatory protein p21 was stimulated within 5 to 10 min by cisplatin in p53-positive LX-1 small cell lung carcinoma cells, and this effect was blocked by NAC [29].
• Furthermore, IL-6 variants were capable of down-regulating the G1 cell cycle regulatory protein cyclin D1 expression [30].
• CDK2 is a key cell cycle regulatory protein that controls the transition of cells from G(1) to S phase [31].

Other interactions of RCC1

• The amino-terminal half of RPGR is homologous to regulator of chromosome condensation (RCC1), the nucleotide exchange factor for the small GTP-binding protein Ran [32].
• We now report that RanBP3 associates with the Ran-specific guanine nucleotide exchange factor, regulator of chromosome condensation 1 (RCC1) [24].
• RanBP3 could also promote binding of Crm1 to RCC1 in the presence of Ran [24].
• Chromatin docking and exchange activity enhancement of RCC1 by histones H2A and H2B [14].
• The human CHC1 gene encoding RCC1 (regulator of chromosome condensation) (CHC1) is localized to human chromosome 1p36.1 [33].

Analytical, diagnostic and therapeutic context of RCC1

• Crystallization and preliminary X-ray analysis of human RCC1, the regulator of chromosome condensation [20].
• Microinjection of wild-type or Q69L Ran markedly slowed the mobility of GFP-RCC1, whereas T24N Ran (defective in nucleotide loading) decreased it further still [22].
• We found significant alterations in the mobility of intranuclear GFP-RCC1 after treatment with agents that disrupt different Ran-dependent nuclear export pathways [22].
• The 131I-labeled anti-breast cancer antibody (RCC-1; 400 micrograms) and cold iodine-labeled "blocking" antibody (Ly-2.1; 2 mg which is nonreactive with breast cancer) were injected s.c. into both arms and scintigraphy images were obtained 16-18 h after the injection, using the axilla contralateral to the side of the breast cancer as the control [34].
• Cell cycle regulatory proteins were studied by western blot and reverse transcription-polymerase chain reaction [35].

References