CN1274828C - Mouse derived EPOR outer cell region and human NOK intracell region infused acceptor and coding gene and uses - Google Patents
Mouse derived EPOR outer cell region and human NOK intracell region infused acceptor and coding gene and uses Download PDFInfo
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- CN1274828C CN1274828C CN 200410037889 CN200410037889A CN1274828C CN 1274828 C CN1274828 C CN 1274828C CN 200410037889 CN200410037889 CN 200410037889 CN 200410037889 A CN200410037889 A CN 200410037889A CN 1274828 C CN1274828 C CN 1274828C
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Abstract
The present invention discloses a jogged recipient of a mouse derived EPOR extracellular region and an anthropogenic NOK intracellular region, a coding gene and application. The present invention aims to provide a jogged recipient of a mouse derived EPOR (erythropoietin recipient) extracellular region and an anthropogenic NOK (novel cancer gene with kinase functional domain) intracellular region, a coding gene and a cell line which can express the recipient. The jogged recipient of a mouse derived EPOR extracellular region and an anthropogenic NOK intracellular region, which is provided by the present invention, comprises an amino acid residue sequence of which the SEQ ID in a sequence table is No. 2, or comprises a protein which is derived from the amino acid residue sequence with the SEQ ID of No. 2 through the substitution, deletion or addition of one or several amino acid residues, and the protein has the same activity as that of the amino acid residue with the SEQ ID of No. 2. The stable expression cell line of the jogged recipient of a mouse derived EPOR extracellular region and an anthropogenic NOK intracellular region, of which the BaF3-EPOR/NOK CGMCC is No. 1144, can be used as a model tool at a cellular level for screening medicines resisting the generation and the transition of tumor.
Description
Technical field
The present invention relates to a kind of mouse source EPOR extracellular region and people source NOK intracellular region Chimerical receptor and encoding gene and application, particularly a kind of mouse source EPOR (erythropoietin receptor) extracellular region and people source the NOK novel oncogene of territory (band kinase function) intracellular region Chimerical receptor and encoding gene and can express the clone of this receptor.
Background technology
Protein tyrosine kinase receptor (PTKR) plays an important role in various cell regulate and control levels and human body different developmental phases, such as the processes such as propagation, differentiation and anti-apoptosis that participate in cell.Typical PTKR structure shows as the single span membranin on the cytolipin bilayer, is divided into extracellular region, strides film district and intracellular region.Extracellular region has the specific recognition site of respective ligand, plays an important role in the binding partner process.Intracellular region contains the Tyrosylprotein kinase functional domain, participates in the signal transduction of the phosphorylation process, particularly mitogen of interior signal transduction of born of the same parents and acceptor, adaptin.PTKR causes genetic diseases and tumour in intracellular unconventionality expression regular meeting.Therefore, proteic being expressed in of PTKR is subjected to strict regulation and control in the human body.So far, it is relevant to have at least 18 kinds of PTKR and tumour to transform, and can be used as oncogene.Important example comprises: growth factor receptors (PDGFR), insulin receptor (InsR) and the hepatocyte growth factor receptor (Met) etc. in fibroblast growth factor acceptor (FGFR), EGF-R ELISA (EGFR), thrombocyte source.
Studies show that part PTKR aberrant splicing varient is relevant with the generation of tumour.Such as separable to lacking the solubility FGFR3 molecule of all striding the film district from human osteosarcoma and breast cancer cell.And in stomach cancer cell, a kind of 49 amino acid whose disappearances that meet encoding histone can cause the constitutively activate of Ron tyrosine acceptor.People are separated to a kind of novel FGFR4 splicing variants from pituitary tumor recently, are referred to as ptd-FGFR4.This splicing variants lacks most FGFR4 acceptor extracellular region, and does not comprise signal peptide, causes this maturation protein only to be expressed at endochylema.Overexpression ptd-FGFR4 can cause cell transformation.In the mouse body, carry out tissue specific expression by the transgenosis mode and can form pituitary tumor.In addition, utilize N end and C terminal specific antibody, it is found that the Met expression of receptor that N end disappearance is also arranged in the pernicious flesh bone of the part knurl clinical patient sample.
Erythropoietin (EPO) and acceptor (EPOR) thereof play a crucial role in the propagation of normal marrow CFU-E and atomization.EPOR is a typical I type cytokines receptor superfamily member.The aminoterminal of this quasi-molecule extracellular region has four cysteine residues usually, and extracellular region carboxyl terminal closely stride the film zone position a tryptophane-Serine-X-tryptophane-Serine motif (WSXWS motif) arranged usually.This motif plays an important role in the ligands specific recognition process.This receptoroid intracellular region is closely striden the film district often has conservative proline(Pro) to be rich in functional domain, abbreviates Box1 as, and far strides the Box2 functional domain that the film zone position often cannot not have conservatively.The activation of EPOR need form homodimer usually, and activates intracytoplasmic adaptin such as JAK2 etc. by Box1 and Box2, makes transcription factor phosphorylations such as STAT5, thereby acts on the expression of target gene promoters regulation and control downstream gene.At present, people are often merged the intracellular region of the extracellular region of EPOR with new receptor in the function course of research novel cytokine acceptor.Which intracellular signal path the activation that the advantage of this Chimerical receptor is to utilize the specific effect of EPO part and acceptor thereof to study function, particularly Chimerical receptor in the unknown acceptor born of the same parents can activate.
Summary of the invention
The purpose of this invention is to provide a kind of mouse source EPOR extracellular region and people source NOK intracellular region Chimerical receptor and encoding gene thereof.
Mouse source EPOR extracellular region and people source NOK intracellular region Chimerical receptor name are called EPOR/NOK, and it is to have SEQ ID № in the sequence table: 2 amino acid residue sequence.
SEQ ID № in the sequence table: 2 protein is made up of 650 amino-acid residues.In actual applications, for the ease of detecting, its carboxyl terminal also has the FLAG label, and the aminoacid sequence of the EPOR/NOK of this band FLAG label is shown in the sequence in the sequence table 4, sequence 4 is made up of 658 amino-acid residues, is the FLAG label from the 651st-658 amino acids residue of aminoterminal.
Mouse source EPOR extracellular region and people source NOK intracellular region Chimerical receptor EPOR/NOK encoding gene have one of following nucleotide sequences:
1) the SEQ ID № in the sequence table: 1;
2) SEQ ID № in the code sequence tabulation: the polynucleotide of 2 protein sequences.
SEQ ID № in the sequence table: 1 by 1953 based compositions, and its open reading frame is from the 1st-1953 bit base of 5 ' end; From the 1st-750 bit base of 5 ' end is mouse source EPOR extracellular region encoding sequence; From the 751st-758 bit base of 5 ' end is external source Not I restriction enzyme site; Stride the encoding sequence of film district and intracellular region for the NOK gene from the 759th-1950 bit base of 5 ' end.
Wherein, (Novel Oncogene withKinase-domain is the new gene that is obtained by the inventor clone NOK) to the novel oncogene NOK gene in band kinase function territory, people source, and it is to have the dna sequence dna shown in the sequence 5 in the sequence table.Sequence 5 is by 1269 based compositions, and its open reading frame is from the 1st-1269 bit base of 5 ' end.
In actual applications, for the ease of detecting, the encoding gene that also has the FLAG label at its 3 ' end, the nucleotide sequence of the encoding gene of this band FLAG label is shown in the sequence in the sequence table 3, sequence 3 is the encoding gene of FLAG label by 1977 based compositions from the 1951st-1977 bit base of 5 ' end.
The carrier and the clone that contain mouse source EPOR extracellular region and people source NOK intracellular region Chimerical receptor EPOR/NOK encoding gene; as pcDNA3 (EPOR/NOK-H) and on May 9th, 2004 be preserved in China Committee for Culture Collection of Microorganisms common micro-organisms center (be called for short CGMCC), preserving number is the BaF3-EPOR/NOK clone of CGMCC № 1144, all belongs to protection scope of the present invention.
Experiment showed, that the EPOR/NOK gene causes this cell to transform in the expression of BaF3 cytotostatic, makes the BaF3 cell be converted into dependent/non-dependent by interleukin (IL-3) dependency; Behind the EPOR/NOK stable expression cell line BaF3-EPOR/NOK subcutaneous vaccination nude mice, can cause the inoculation position tumour to generate and internal organs transfer at a distance, show as the malignant tumour characteristics.BaF3-EPOR/NOK inoculation nude mice can be used as the research tumour and takes place and metastasis, and the animal pattern of screening antitumor generation and diversion medicaments.The modeling tool that BaF3-EPOR/NOK can be used as cell levels is used to screen antitumor generation and diversion medicaments, plays a significant role in will detecting in the drug effect of screening anti-tumor medicine and antitumor drug.
Description of drawings
The NOK gene product of Fig. 1 for from the total RNA of tonsilla tumour, obtaining through the RT-PCR amplification
Fig. 2 analyzes the EPOR/NOK Chimerical receptor for DAS strides film district forecasting software
Fig. 3 is an EPOR/NOK protein tyrosine kinase functional domain analytical results
Fig. 4 is for using the proteic expression of EPOR/NOK in mouse source FLAG antibody test BaF3-p3 and the BaF3-EPOR/NOK stabilized cell
Fig. 5 is the growth curve of BaF3-EPOR/NOK under starvation conditions
Fig. 6 forms the photo of colony in the semisolid medium that does not have serum and WEHI-3B for the BaF3-EPOR/NOK cell
Fig. 7 is that BaF3-EPOR/NOK subcutaneous vaccination nude mice becomes the knurl photo
Behind Fig. 8 BaF3-EPOR/NOK subcutaneous vaccination nude mice, the HE coloration result synoptic diagram of tumour cell internal organs transfer at a distance
Embodiment
The acquisition of embodiment 1, EPOR/NOK encoding gene
With primer 5 '-TATAGCGATATCATGGACAAACTCAGGGTGCC-3 ' and 5 '-TATAGCGCGGCCGCGAGAGGGTCCAGGTCGCTA-3 ', with pMX-EPOR (pBabe-EPO-R) is template (PNAS, Vol.93, p8324-8328, August 1996), in following reaction system: the 50ng template DNA, every kind of primer of 100pmol, 1 * amplification buffer, every kind of dNTP of 200 μ mol/L, the 1 high-fidelity Taq of unit enzyme; Under the cycling program: 94 ℃ 5 minutes, 94 ℃ 30 seconds, 55 ℃ 30 seconds, 72 ℃ 1 minute, 35 circulations, 72 ℃ of extensions in 10 minutes, amplification mouse erythropoietin receptor (EPOR) extracellular region, utilize EcoR V and Not I subclone between the EcoR V and Not I site of pcDNA3 (available from Invitrogen company) fragment that obtains, obtain plasmid pcDNA3 (EPOR).
The NOK full-length cDNA obtains through RT-PCR from the total RNA of human tonsil's tumour, and concrete steps are as follows: extract the total RNA of human tonsil's tumour according to a conventional method, then with 5 '-TATAAAGCTTATGGGCATGATGACACGGATGCT-3 ' and 5 '-TATACTCGAG
TCAGGCGTAGTCGGGCACGTCGTAGGGGTAAAGCATGCTATAGTTGTA-3 ' is primer (underscore is that HA expresses label), reaction conditions carries out (Takara) according to the operation instruction of single stage method RT-PCR, directly subclone is to T carrier (available from Promega company) behind PCR product (Fig. 1) purifying that obtains, and enzyme checks order after cutting evaluation again.With the RT-PCR product that checked order through subclone behind HindIII and the XhoI double digestion to pcDNA3 (available from Invitrogen company), constitute pcDNA3 (NOK-H) expression plasmid.
With primer 5 '-TATAGCGGCCGCAGTGATTATCGTCCCAACTTT-3 ' and 5 '-TATACCAGTGTGCTGGTCACTTGTCA TCGTCGTCCTTGTAGTCAAGCATGCTATAGTTGTAGA-3 ' is a template with pcDNA3 (NOK-H), in following reaction system: the 50ng template DNA, every kind of primer of 100pmol, 1 * amplification buffer, every kind of dNTP of 200 μ mol/L, the 1 high-fidelity Taq of unit enzyme; Under cycling program: 94 ℃ 5 minutes, 94 ℃ 30 seconds, 55 ℃ 30 seconds, 72 ℃ 1 minute, 35 circulations, 72 ℃ were extended in 10 minutes, amplification people NOK-H strides film district and intracellular region, utilize Not I and BstX I subclone between the Not I and BstX I site of pcDNA3 (EPOR) fragment that obtains, screening obtains complete integrative gene expression vector pcDNA3 (EPOR/NOK-H), and order-checking shows that this fusion gene has the nucleotide sequence of sequence 1 in the sequence table.This fusion gene C-terminal carries FLAG label (sequence 3 in the sequence table), can be by mouse M2 antibody recognition.
EPOR/NOK is the protein with amino acid residue sequence of sequence 2 in the sequence table, and it is single transmembrane molecule that DAS strides film forecasting software analysis EPOR/NOK, strides the film district and is positioned at from aminoterminal 249-277 amino-acid residue (Fig. 2).EPOR/NOK has typical Tyrosylprotein kinase functional domain (from aminoterminal 333-600 amino-acid residue) (Fig. 3)
The structure of embodiment 2, BaF3-EPOR/NOK stable cell lines
Centrifugal 1 * 106 wild-type BaF3 cell of collecting is resuspended in 0.5ml serum-free RPMI-1640 nutrient solution.With the pcDNA3 (EPOR/NOK-H) and BaF3 cytomixis that obtains among the 3 μ g embodiment 1, ice bath carried out electricity with ECM399 (BTX company) electroporation and changes after 10 minutes.Electricity commentaries on classics condition is 200-230V, and electric current is the 25-35 millisecond.Cell behind the electrotransfection is grown in the full substratum of RPMI-1640.Under the screening of G418, obtain to stablize expression of exogenous gene.Because plasmid pcDNA3 carries the plain resistant gene of new enzyme, stabilized cell screens under 500 μ g/ml G418.Changed a not good liquor in per three days, cultured continuously increased in the 100mm culture dish after three weeks, obtained clone BaF3-EPOR/NOK CGMCC № 1144.
Because the carboxyl terminal of EPOR/NOK gene has merged a FLAG label, positive cell clone can be hybridized (Western Blot) by protein blot and is detected.Forward on the nitrocellulose filter after 10%SDS/PAGE separates Deng the BaF3-EPOR/NOK of protein content and the cell pyrolysis liquid of BaF3-P3 (BaF3 of pcDNA3.0 empty carrier stable transfection) contrast.Monoclonal antibody (Santa Cruz Biotechnology) with the anti-FLAG label in mouse source is anti-hybridization, with fluorescein-labeled sheep source anti-mouse antibody (Amersham Biosciences UK Limited) is two anti-, carrying out hybridization signal with the chemiluminescent substrate of ECL at last amplifies, the result as shown in Figure 4, show that clone BaF3-EPOR/NOK has specificity EPOR/NOK protein expression, molecular weight is about 68kD.
Embodiment 4, EPOR/NOK gene make the BaF3 cell be converted into dependent/non-dependent by interleukin (IL-3) dependency
The BaF3 cell is the mouse pre B cell, and the stimulation that needs interleukin could be bred down.Do not having serum and do not having the RPMI-1640 of WEHI-3B (to mix
3The H Thymine deoxyriboside) cultivated 3 days at 37 ℃ in the nutrient solution, [
3H] mix and detect the cell proliferation result as shown in Figure 5, showing is not having serum and is not having in the RPMI-1640 nutrient solution of WEHI-3B, BaF3-EPOR/NOK can significantly breed more than 3 days, and BaF3-P3 (BaF3 of pcDNA3.0 empty carrier stable transfection) contrasts owing to the stimulation that needs IL-3, thereby cell is not almost bred.Explanation is stably express EPOR/NOK gene in the BaF3 cell, and BaF3-EPOR/NOK also can be bred under the situation that does not have WEHI-3B conditioned medium (IL-3 is provided).
Embodiment 5, BaF3-EPOR/NOK have the characteristic that the non-dependence of grappling increases under ' hunger ' culture condition
The growth of stabilized cell in semisolid medium is to detect one of foundation of cell transformation characteristic.With the BaF3-EPOR/NOK cell with 1 * 10
5The concentration of individual cell/ml substratum is suspended in the 0.4% agarose substratum of 60mm culture dish splendid attire, is layered on 0.8% the agarose substratum.Agarose substratum RPMI-1640 inoculum preparation wherein contains 5%FBS and 400 μ g/ml G418.The negative contrast of BaF3 (BaF3-p3) with pcDNA3.0 empty carrier stable transfection.Do not having serum and do not having under the condition of WEHI-3B supernatant, placing 37 ℃ of incubators that contain 5% carbonic acid gas to cultivate.After three weeks, with the colony number of cell of inverted microscope calculated diameter greater than 0.1mm, the result shows that BaF3-EPOR/NOK has tangible colony to generate as shown in Figure 6 under ' hunger ' culture condition.Statistics is as shown in table 1, shows stably express EPOR/NOK in the BaF3 cell, and the multiplication characteristic of BaF3 cell is changed, and has the characteristics of tumour cell.
The colony that table 1, BaF3 stabilized cell tie up in the semi-solid agarose substratum generates test
| BaF3 clone | Cell count | Colony number (standard deviation) |
| BaF3-p3 BaF3-EPOR/ | 1×10 5 1×10 5 | 0(0) 102(10) |
Annotate: the colony number is the mean+SD of three parallel laboratory tests
Embodiment 6, BaF3-EPOR/NOK cell have the tumour formation characteristic, and the subcutaneous vaccination nude mice can cause malignant tumour to generate
Become the concrete steps of knurl experiment to be in the body, with 1 * 10
7BaF3-EPOR/NOK stable cell lines subcutaneous injection 4-6 week is gone thymus gland Balb-c nude mice, and the injection site is a nude mice right forearm armpit skin.The negative contrast of BaF3 cell (BaF3-p3) with stably express pcDNA3.0 empty carrier.Six nude mices of each injection cell.Each experimental group comprises three female mouse (F1, F2, F3) and three male mouse (M1, M2, M3).Visible inoculation position is subcutaneous after 7-10 days has obvious tumour to form (Fig. 7) for injection BaF3-EPOR/NOK cell.Control group with become the knurl situation as shown in Figure 7 after test group inoculated for three weeks.Inoculation BaF3-EPOR/NOK cell is mouse whole body appearance depletion after one month, is slow in action death in 35-40 days.The BaF3-EPOR/NOK cell presents malignant growth trend in nude mouse, become the wettability growth at injection site skeletal muscle, and liver and spleen obviously increase, and causes internal organs such as liver, spleen, kidney and lungs transfers (Fig. 8 and table 2) at a distance.Among Fig. 8, arrow is designated as the metastases kitchen range.
Table 2, BaF3-NOK generate situation in the nude mice tumour
| The clone sex cell count time (my god) mouse name tumour (gram) liver (gram) spleen (gram) |
| BaF3-p3 M 1.0×10 7 28 M-1 - 1.66 0.10 M-2 - 1.37 0.12 M-3 - 1.45 0.08 F 1.0×10 7 28 F-1 - 1.24 0.10 F-2 - 0.95 0.05 F-3 - 1.11 0.08 Average a - 1.30 0.09 ±0.25 ±0.02 BaF3- M 1.0×10 7 28 M-1 1.81 2.00 0.20 EPOR/NOK M-2 1.16 1.84 0.31 M-3 2.55 2.79 0.27 F 1.0×10 7 28 F-1 1.64 1.22 0.12 F-2 1.20 1.21 0.10 F-3 1.49 1.55 0.19 Average a 1.64 1.77 0.20 ±0.51 ±0.59 ±0.08 |
aRepresent the mean+SD of nude mice
Sequence table
<160>5
<210>1
<211>1953
<212>DNA
＜213〉artificial sequence
<220>
<223>
<400>1
atggacaaac tcagggtgcc cctctggcct cgggtaggcc ccctctgtct cctacttgct 60
ggggcagcct gggcaccttc acccagcctc ccggacccca agtttgagag caaagcggcc 120
ctgctggcat cccggggctc cgaagaactt ctgtgcttca cccaacgctt ggaagacttg 180
gtgtgtttct gggaggaagc ggcgagctcc gggatggact tcaactacag cttctcatac 240
cagctcgagg gtgagtcacg aaagtcatgt agcctgcacc aggctcccac cgtccgcggc 300
tccgtgcgtt tctggtgttc actgccaaca gcggacacat cgagttttgt gccgctggag 360
ctgcaggtga cggaggcgtc cggttctcct cgctatcacc gcatcatcca tatcaatgaa 420
gtagtgctcc tggacgcccc cgcggggctg ctggcgcgcc gggcagaaga gggcagccac 480
gtggtgctgc gctggctgcc acctcctgga gcacctatga ccacccacat ccgatatgaa 540
gtggacgtgt cggcaggcaa ccgggcagga gggacacaaa gggtggaggt cctggaaggc 600
cgcactgagt gtgttctgag caacctgcgg ggcgggacgc gctacacctt cgctgttcga 660
gcgcgcatgg ccgagccgag cttcagcgga ttctggagtg cctggtctga gcccgcgtca 720
ctactgaccg ctagcgacct ggaccctctc gcggccgcag tgattatcgt cccaactttg 780
ttggttacta tcttcctcat ccttcttggg gtcatcctgt ggctttttat cagagaacaa 840
agaactcaac agcagcgttc tggacctcaa ggcattgccc ctgttcctcc acctagggac 900
ctaagctggg aagcaggaca tggaggaaat gtggctttgc cacttaagga gacatccgtg 960
gaaaactttc tgggagctac cacacctgcc ctggctaagc tgcaggtgcc gcgggagcaa 1020
ctctctgaag ttctggagca gatttgcagc ggtagctgtg ggcccatctt tcgagccaat 1080
atgaacactg gggacccttc taagcccaag agtgttattc tcaaggcttt aaaagaacca 1140
gctgggctcc atgaggtaca agatttctta gggcgaatcc aattccatca atacctgggg 1200
aaacacaaaa acctggtgca gctggaaggc tgctgcactg aaaagctgcc actctatgtg 1260
gtgttggagg atgtggccca gggggacctg cttagctttc tctggacctg tcggcgggat 1320
gtgatgacta tggatggtct tctctatgat ctcacagaaa aacaagtata tcacatcgga 1380
aagcaggtcc ttttggcgct ggaattcctg caggagaagc atttgttcca tggggatgtg 1440
gcagccagga atattctgat gcaaagtgat ctcactgcta agctctgtgg attaggcctg 1500
gcttatgaag tttacacccg aggggccatc tcctctactc aaaccatacc tctcaagtgg 1560
cttgccccag aacggcttct cctgagacct gctcgcatca gagcagatgt ctggtctttt 1620
gggatcctgc tctatgagat ggtgactcta ggagcaccac cgtatcctga agtccctcct 1680
accagcatcc tagagcatct ccaaagaagg aaaatcatga agagacccag tagctgcaca 1740
cataccatgt acagtatcat gaagtcctgc tggcgctggc gtgaggctga ccgcccctca 1800
cctagagagc tgcgcttgcg cctagaagct gccattaaaa ctgcagatga cgaggctgtg 1860
ttacaagtac cagagttggt ggtacctgaa ctgtatgcag ctgtggccgg catcagagtg 1920
gagagcctct tctacaacta tagcatgctt tga 1953
<210>2
<211>650
<212>PRT
＜213〉artificial sequence
<220>
<223>
<400>2
Met Asp Lys Leu Arg Val Pro Leu Trp Pro Arg Val Gly Pro Leu Cys
1 5 10 15
Leu Leu Leu Ala Gly Ala Ala Trp Ala Pro Ser Pro Ser Leu Pro Asp
20 25 30
Pro Lys Phe Glu Ser Lys Ala Ala Leu Leu Ala Ser Arg Gly Ser Glu
35 40 45
Glu Leu Leu Cys Phe Thr Gln Arg Leu Glu Asp Leu Val Cys Phe Trp
50 55 60
Glu Glu Ala Ala Ser Ser Gly Met Asp Phe Asn Tyr Ser Phe Ser Tyr
65 70 75 80
Gln Leu Glu Gly Glu Ser Arg Lys Ser Cys Ser Leu His Gln Ala Pro
85 90 95
Thr Val Arg Gly Ser Val Arg Phe Trp Cys Ser Leu Pro Thr Ala Asp
100 105 110
Thr Ser Ser Phe Val Pro Leu Glu Leu Gln Val Thr Glu Ala Ser Gly
115 120 125
Ser Pro Arg Tyr His Arg Ile Ile His Ile Asn Glu Val Val Leu Leu
130 135 140
Asp Ala Pro Ala Gly Leu Leu Ala Arg Arg Ala Glu Glu Gly Ser His
145 150 155 160
Val Val Leu Arg Trp Leu Pro Pro Pro Gly Ala Pro Met Thr Thr His
165 170 175
Ile Arg Tyr Glu Val Asp Val Ser Ala Gly Asn Arg Ala Gly Gly Thr
180 185 190
Gln Arg Val Glu Val Leu Glu Gly Arg Thr Glu Cys Val Leu Ser Asn
195 200 205
Leu Arg Gly Gly Thr Arg Tyr Thr Phe Ala Val Arg Ala Arg Met Ala
210 215 220
Glu Pro Ser Phe Ser Gly Phe Trp Ser Ala Trp Ser Glu Pro Ala Ser
225 230 235 240
Leu Leu Thr Ala Ser Asp Leu Asp Pro Leu Ala Ala Ala Val Ile Ile
245 250 255
Val Pro Thr Leu Leu Val Thr Ile Phe Leu Ile Leu Leu Gly Val Ile
260 265 270
Leu Trp Leu Phe Ile Arg Glu Gln Arg Thr Gln Gln Gln Arg Ser Gly
275 280 285
Pro Gln Gly Ile Ala Pro Val Pro Pro Pro Arg Asp Leu Ser Trp Glu
290 295 300
Ala Gly His Gly Gly Asn Val Ala Leu Pro Leu Lys Glu Thr Ser Val
305 310 315 320
Glu Asn Phe Leu Gly Ala Thr Thr Pro Ala Leu Ala Lys Leu Gln Val
325 330 335
Pro Arg Glu Gln Leu Ser Glu Val Leu Glu Gln Ile Cys Ser Gly Ser
340 345 350
Cys Gly Pro Ile Phe Arg Ala Asn Met Asn Thr Gly Asp Pro Ser Lys
355 360 365
Pro Lys Ser Val Ile Leu Lys Ala Leu Lys Glu Pro Ala Gly Leu His
370 375 380
Glu Val Gln Asp Phe Leu Gly Arg Ile Gln Phe His Gln Tyr Leu Gly
385 390 395 400
Lys His Lys Asn Leu Val Gln Leu Glu Gly Cys Cys Thr Glu Lys Leu
405 410 415
Pro Leu Tyr Val Val Leu Glu Asp Val Ala Gln Gly Asp Leu Leu Ser
420 425 430
Phe Leu Trp Thr Cys Arg Arg Asp Val Met Thr Met Asp Gly Leu Leu
435 440 445
Tyr Asp Leu Thr Glu Lys Gln Val Tyr His Ile Gly Lys Gln Val Leu
450 455 460
Leu Ala Leu Glu Phe Leu Gln Glu Lys His Leu Phe His Gly Asp Val
465 470 475 480
Ala Ala Arg Asn Ile Leu Met Gln Ser Asp Leu Thr Ala Lys Leu Cys
485 490 495
Gly Leu Gly Leu Ala Tyr Glu Val Tyr Thr Arg Gly Ala Ile Ser Ser
500 505 510
Thr Gln Thr Ile Pro Leu Lys Trp Leu Ala Pro Glu Arg Leu Leu Leu
515 520 525
Arg Pro Ala Arg Ile Arg Ala Asp Val Trp Ser Phe Gly Ile Leu Leu
530 535 540
Tyr Glu Met Val Thr Leu Gly Ala Pro Pro Tyr Pro Glu Val Pro Pro
545 550 555 560
Thr Ser Ile Leu Glu His Leu Gln Arg Arg Lys Ile Met Lys Arg Pro
565 570 575
Ser Ser Cys Thr His Thr Met Tyr Ser Ile Met Lys Ser Cys Trp Arg
580 585 590
Trp Arg Glu Ala Asp Arg Pro Ser Pro Arg Glu Leu Arg Leu Arg Leu
595 600 605
Glu Ala Ala Ile Lys Thr Ala Asp Asp Glu Ala Val Leu Gln Val Pro
610 615 620
Glu Leu Val Val Pro Glu Leu Tyr Ala Ala Val Ala Gly Ile Arg Val
625 630 635 640
Glu Ser Leu Phe Tyr Asn Tyr Ser Met Leu
645 650
<210>3
<211>1977
<212>DNA
＜213〉artificial sequence
<220>
<223>
<400>3
atggacaaac tcagggtgcc cctctggcct cgggtaggcc ccctctgtct cctacttgct 60
ggggcagcct gggcaccttc acccagcctc ccggacccca agtttgagag caaagcggcc 120
ctgctggcat cccggggctc cgaagaactt ctgtgcttca cccaacgctt ggaagacttg 180
gtgtgtttct gggaggaagc ggcgagctcc gggatggact tcaactacag cttctcatac 240
cagctcgagg gtgagtcacg aaagtcatgt agcctgcacc aggctcccac cgtccgcggc 300
tccgtgcgtt tctggtgttc actgccaaca gcggacacat cgagttttgt gccgctggag 360
ctgcaggtga cggaggcgtc cggttctcct cgctatcacc gcatcatcca tatcaatgaa 420
gtagtgctcc tggacgcccc cgcggggctg ctggcgcgcc gggcagaaga gggcagccac 480
gtggtgctgc gctggctgcc acctcctgga gcacctatga ccacccacat ccgatatgaa 540
gtggacgtgt cggcaggcaa ccgggcagga gggacacaaa gggtggaggt cctggaaggc 600
cgcactgagt gtgttctgag caacctgcgg ggcgggacgc gctacacctt cgctgttcga 660
gcgcgcatgg ccgagccgag cttcagcgga ttctggagtg cctggtctga gcccgcgtca 720
ctactgaccg ctagcgacct ggaccctctc gcggccgcag tgattatcgt cccaactttg 780
ttggttacta tcttcctcat ccttcttggg gtcatcctgt ggctttttat cagagaacaa 840
agaactcaac agcagcgttc tggacctcaa ggcattgccc ctgttcctcc acctagggac 900
ctaagctggg aagcaggaca tggaggaaat gtggctttgc cacttaagga gacatccgtg 960
gaaaactttc tgggagctac cacacctgcc ctggctaagc tgcaggtgcc gcgggagcaa 1020
ctctctgaag ttctggagca gatttgcagc ggtagctgtg ggcccatctt tcgagccaat 1080
atgaacactg gggacccttc taagcccaag agtgttattc tcaaggcttt aaaagaacca 1140
gctgggctcc atgaggtaca agatttctta gggcgaatcc aattccatca atacctgggg 1200
aaacacaaaa acctggtgca gctggaaggc tgctgcactg aaaagctgcc actctatgtg 1260
gtgttggagg atgtggccca gggggacctg cttagctttc tctggacctg tcggcgggat 1320
gtgatgacta tggatggtct tctctatgat ctcacagaaa aacaagtata tcacatcgga 1380
aagcaggtcc ttttggcgct ggaattcctg caggagaagc atttgttcca tggggatgtg 1440
gcagccagga atattctgat gcaaagtgat ctcactgcta agctctgtgg attaggcctg 1500
gcttatgaag tttacacccg aggggccatc tcctctactc aaaccatacc tctcaagtgg 1560
cttgccccag aacggcttct cctgagacct gctcgcatca gagcagatgt ctggtctttt 1620
gggatcctgc tctatgagat ggtgactcta ggagcaccac cgtatcctga agtccctcct 1680
accagcatcc tagagcatct ccaaagaagg aaaatcatga agagacccag tagctgcaca 1740
cataccatgt acagtatcat gaagtcctgc tggcgctggc gtgaggctga ccgcccctca 1800
cctagagagc tgcgcttgcg cctagaagct gccattaaaa ctgcagatga cgaggctgtg 1860
ttacaagtac cagagttggt ggtacctgaa ctgtatgcag ctgtggccgg catcagagtg 1920
gagagcctct tctacaacta tagcatgctt gactacaagg acgacgatga caagtga 1977
<210>4
<211>658
<212>PRT
＜213〉artificial sequence
<220>
<223>
<400>4
Met Asp Lys Leu Arg Val Pro Leu Trp Pro Arg Val Gly Pro Leu Cys
1 5 10 15
Leu Leu Leu Ala Gly Ala Ala Trp Ala Pro Ser Pro Ser Leu Pro Asp
20 25 30
Pro Lys Phe Glu Ser Lys Ala Ala Leu Leu Ala Ser Arg Gly Ser Glu
35 40 45
Glu Leu Leu Cys Phe Thr Gln Arg Leu Glu Asp Leu Val Cys Phe Trp
50 55 60
Glu Glu Ala Ala Ser Ser Gly Met Asp Phe Asn Tyr Ser Phe Ser Tyr
65 70 75 80
Gln Leu Glu Gly Glu Ser Arg Lys Ser Cys Ser Leu His Gln Ala Pro
85 90 95
Thr Val Arg Gly Ser Val Arg Phe Trp Cys Ser Leu Pro Thr Ala Asp
100 105 110
Thr Ser Ser Phe Val Pro Leu Glu Leu Gln Val Thr Glu Ala Ser Gly
115 120 125
Ser Pro Arg Tyr His Arg Ile Ile His Ile Asn Glu Val Val Leu Leu
130 135 140
Asp Ala Pro Ala Gly Leu Leu Ala Arg Arg Ala Glu Glu Gly Ser His
145 150 155 160
Val Val Leu Arg Trp Leu Pro Pro Pro Gly Ala Pro Met Thr Thr His
165 170 175
Ile Arg Tyr Glu Val Asp Val Ser Ala Gly Asn Arg Ala Gly Gly Thr
180 185 190
Gln Arg Val Glu Val Leu Glu Gly Arg Thr Glu Cys Val Leu Ser Asn
195 200 205
Leu Arg Gly Gly Thr Arg Tyr Thr Phe Ala Val Arg Ala Arg Met Ala
210 215 220
Glu Pro Ser Phe Ser Gly Phe Trp Ser Ala Trp Ser Glu Pro Ala Ser
225 230 235 240
Leu Leu Thr Ala Ser Asp Leu Asp Pro Leu Ala Ala Ala Val Ile Ile
245 250 255
Val Pro Thr Leu Leu Val Thr Ile Phe Leu Ile Leu Leu Gly Val Ile
260 265 270
Leu Trp Leu Phe Ile Arg Glu Gln Arg Thr Gln Gln Gln Arg Ser Gly
275 280 285
Pro Gln Gly Ile Ala Pro Val Pro Pro Pro Arg Asp Leu Ser Trp Glu
290 295 300
Ala Gly His Gly Gly Asn Val Ala Leu Pro Leu Lys Glu Thr Ser Val
305 310 315 320
Glu Asn Phe Leu Gly Ala Thr Thr Pro Ala Leu Ala Lys Leu Gln Val
325 330 335
Pro Arg Glu Gln Leu Ser Glu Val Leu Glu Gln Ile Cys Ser Gly Ser
340 345 350
Cys Gly Pro Ile Phe Arg Ala Asn Met Asn Thr Gly Asp Pro Ser Lys
355 360 365
Pro Lys Ser Val Ile Leu Lys Ala Leu Lys Glu Pro Ala Gly Leu His
370 375 380
Glu Val Gln Asp Phe Leu Gly Arg Ile Gln Phe His Gln Tyr Leu Gly
385 390 395 400
Lys His Lys Asn Leu Val Gln Leu Glu Gly Cys Cys Thr Glu Lys Leu
405 410 415
Pro Leu Tyr Val Val Leu Glu Asp Val Ala Gln Gly Asp Leu Leu Ser
420 425 430
Phe Leu Trp Thr Cys Arg Arg Asp Val Met Thr Met Asp Gly Leu Leu
435 440 445
Tyr Asp Leu Thr Glu Lys Gln Val Tyr His Ile Gly Lys Gln Val Leu
450 455 460
Leu Ala Leu Glu Phe Leu Gln Glu Lys His Leu Phe His Gly Asp Val
465 470 475 480
Ala Ala Arg Asn Ile Leu Met Gln Ser Asp Leu Thr Ala Lys Leu Cys
485 490 495
Gly Leu Gly Leu Ala Tyr Glu Val Tyr Thr Arg Gly Ala Ile Ser Ser
500 505 510
Thr Gln Thr Ile Pro Leu Lys Trp Leu Ala Pro Glu Arg Leu Leu Leu
515 520 525
Arg Pro Ala Arg Ile Arg Ala Asp Val Trp Ser Phe Gly Ile Leu Leu
530 535 540
Tyr Glu Met Val Thr Leu Gly Ala Pro Pro Tyr Pro Glu Val Pro Pro
545 550 555 560
Thr Ser Ile Leu Glu His Leu Gln Arg Arg Lys Ile Met Lys Arg Pro
565 570 575
Ser Ser Cys Thr His Thr Met Tyr Ser Ile Met Lys Ser Cys Trp Arg
580 585 590
Trp Arg Glu Ala Asp Arg Pro Ser Pro Arg Glu Leu Arg Leu Arg Leu
595 600 605
Glu Ala Ala Ile Lys Thr Ala Asp Asp Glu Ala Val Leu Gln Val Pro
610 615 620
Glu Leu Val Val Pro Glu Leu Tyr Ala Ala Val Ala Gly Ile Arg Val
625 630 635 640
Glu Ser Leu Phe Tyr Asn Tyr Ser Met Leu Asp Tyr Lys Asp Asp Asp
645 650 655
Asp Lys
658
<210>5
<211>1269
<212>DNA
＜213〉artificial sequence
<220>
<223>
<400>5
atgggcatga cacggatgct cctggaatgc agtctcagtg acaagttgtg tgtcatccag 60
gagaagcagt atgaagtgat tatcgtccca actttgttgg ttactatctt cctcatcctt 120
cttggggtca tcctgtggct ttttatcaga gaacaaagaa ctcaacagca gcgttctgga 180
cctcaaggca ttgcccctgt tcctccacct agggacctaa gctgggaagc aggacatgga 240
ggaaatgtgg ctttgccact taaggagaca tccgtggaaa actttctggg agctaccaca 300
cctgccctgg ctaagctgca ggtgccgcgg gagcaactct ctgaagttct ggagcagatt 360
tgcagcggta gctgtgggcc catctttcga gccaatatga acactgggga cccttctaag 420
cccaagagtg ttattctcaa ggctttaaaa gaaccagctg ggctccatga ggtacaagat 480
ttcttagggc gaatccaatt ccatcaatac ctggggaaac acaaaaacct ggtgcagctg 540
gaaggctgct gcactgaaaa gctgccactc tatgtggtgt tggaggatgt ggcccagggg 600
gacctgctta gctttctctg gacctgtcgg cgggatgtga tgactatgga tggtcttctc 660
tatgatctca cagaaaaaca agtatatcac atcggaaagc aggtcctttt ggcgctggaa 720
ttcctgcagg agaagcattt gttccatggg gatgtggcag ccaggaatat tctgatgcaa 780
agtgatctca ctgctaagct ctgtggatta ggcctggctt atgaagttta cacccgaggg 840
gccatctcct ctactcaaac catacctctc aagtggcttg ccccagaacg gcttctcctg 900
agacctgctc gcatcagagc agatgtctgg tcttttggga tcctgctcta tgagatggtg 960
actctaggag caccaccgta tcctgaagtc cctcctacca gcatcctaga gcatctccaa 1020
agaaggaaaa tcatgaagag acccagtagc tgcacacata ccatgtacag tatcatgaag 1080
tcctgctggc gctggcgtga ggctgaccgc ccctcaccta gagagctgcg cttgcgccta 1140
gaagctgcca ttaaaactgc agatgacgag gctgtgttac aagtaccaga gttggtggta 1200
cctgaactgt atgcagctgt ggccggcatc agagtggaga gcctcttcta caactatagc 1260
atgctttga 1269
Claims (8)
1, a kind of mouse source EPOR extracellular region and people source NOK intracellular region Chimerical receptor are to have SEQ ID № in the sequence table: the protein of 2 amino acid residue sequences.
2, Chimerical receptor according to claim 1, it is characterized in that: the carboxyl terminal of described mouse source EPOR extracellular region and people source NOK intracellular region Chimerical receptor also has the FLAG label, and the Chimerical receptor of the described FLAG of having label has the aminoacid sequence of sequence 4 in the sequence table.
3, mouse source EPOR extracellular region and people source NOK intracellular region Chimerical receptor encoding gene have one of following nucleotide sequences:
1) the SEQ ID № in the sequence table: 1;
2) SEQ ID № in the code sequence tabulation: the polynucleotide of 2 protein sequences.
4, gene according to claim 3 is characterized in that: described mouse source EPOR extracellular region and people source NOK intracellular region Chimerical receptor encoding gene are to have SEQ ID № in the sequence table: 1 nucleotide sequence.
5, gene according to claim 4, it is characterized in that: 3 of described mouse source EPOR extracellular region and people source NOK intracellular region Chimerical receptor encoding gene ' end also has the encoding gene of FLAG label, and the Chimerical receptor encoding gene of described band FLAG label coding gene has SEQ ID № in the sequence table: 3 nucleotide sequence.
6, contain the described expression carrier of claim 3.
7, the transgenic cell line that contains the described gene of claim 3.
8, clone according to claim 7 is characterized in that: described cell is BaF3-EPOR/NOKCGMCC № 1144.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410037889 CN1274828C (en) | 2004-05-13 | 2004-05-13 | Mouse derived EPOR outer cell region and human NOK intracell region infused acceptor and coding gene and uses |
| US11/568,972 US20090222931A1 (en) | 2004-05-13 | 2004-05-13 | Novel identified oncogene with kinase-domain (nok) |
| PCT/CN2005/000669 WO2005111067A1 (en) | 2004-05-13 | 2005-05-13 | A novel identified oncogene with kinase-domain (nok) |
| US13/419,096 US20120288876A1 (en) | 2004-05-13 | 2012-03-13 | Novel identified oncogene with kinase-domain (nok) |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410037889 CN1274828C (en) | 2004-05-13 | 2004-05-13 | Mouse derived EPOR outer cell region and human NOK intracell region infused acceptor and coding gene and uses |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1570108A CN1570108A (en) | 2005-01-26 |
| CN1274828C true CN1274828C (en) | 2006-09-13 |
Family
ID=34481777
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200410037889 Expired - Fee Related CN1274828C (en) | 2004-05-13 | 2004-05-13 | Mouse derived EPOR outer cell region and human NOK intracell region infused acceptor and coding gene and uses |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1274828C (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106065402B (en) * | 2015-04-20 | 2020-11-13 | 中国医学科学院基础医学研究所 | NOK mutant and application thereof in tumor diagnosis, treatment and drug screening |
| CN117305269B (en) * | 2023-09-15 | 2024-04-16 | 湖北工业大学 | Polypeptide based on STYK1 kinase structure and application thereof in preparation of medicines for treating cancers |
-
2004
- 2004-05-13 CN CN 200410037889 patent/CN1274828C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN1570108A (en) | 2005-01-26 |
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