CN102952825B - System and method for enabling the cell apoptosis of chronic myeloid leukaemia - Google Patents
System and method for enabling the cell apoptosis of chronic myeloid leukaemia Download PDFInfo
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Abstract
The invention relates to a system for enabling the cell apoptosis of chronic myeloid leukaemia. The system is formed by connecting two fusion peptides N3R of an adenovirus vector, two compounds AP21967 and fusion peptide F2S of the adenovirus vector together. Through experimental verification, the system can be used for achieving and realizing induction of CML (Chronic Myeloid Leukemia) cell apoptosis, is good in effect, and has great research values on researching the treatment of leukaemia and developing medicaments.
Description
Technical field
The invention belongs to medical basic research field, specifically, relate to a kind of system and method thereof that causes apoptosis of leukemia.
Background technology
Chronic myelocytic leukemia (CML) is a kind of pernicious myeloproliferative disease occurring on early stage pluripotential hemopoietic stem cell.Relate generally to medullary system, clinical manifestation is that in splenomegaly, peripheral blood, granulocyte significantly increases and occurs immature granulocyte.In the clone of getting involved, can find Ph karyomit(e) and (or) bcr-abl fusion gene.The Bcr-Abl fusion rotein of bcr-abl fusion gene coding has the tyrosine kinase activity of constitutively activate, by activating the anti-apoptotic signals such as PI3K, STAT5 inhibited apoptosis significantly, and the conversion of inducing cell, thus cause developing of CML.Clinical application is at present imatinib in the first-line drug of CML treatment, and it passes through the ATP-binding site in competitive binding Bcr-Abl albumen, thereby Bcr-Abl can not be made progress by phosphorylated substrate blocking-up CML.But, still have clinically 1/3 patient not tolerate or resistance imatinib at present, for these needs of patients, seek other alternative medicine.
Summary of the invention
For solving above technical problem, the object of the present invention is to provide a kind of system and method thereof that allows chronic myeloid leukemia cell apoptosis.
The present invention seeks to realize like this:
RATS target Bcr-Abl enters core and borrows the apoptotic project verification of tyrosine kinase activity induction CML according to as follows:
Between 1.Bcr-Abl and c-Abl, demonstrate the difference of significantly thin inner cellular localization and effect, in CML morbidity, play an important role:
Bcr-Abl and c-Abl contain the identical nuclear localization signal relevant to protein localization (nuclear localization signal, NLS) and nuclear export signal (nuclear export signal, NES), but c-Abl can locate in cytoplasm and nucleus, Bcr-Abl is only positioned cytoplasm.The c-Abl that is positioned at core is an important withered induced protein, after its activation, by phosphorylation transcription factor p73, its transcriptional activity is strengthened, and activates caspase apoptotic signal approach, the apoptosis of inducing cell; Be positioned at the Bcr-Abl of endochylema by activating anti-apoptotic signal inhibited apoptosis significantly, the conversion of inducing cell.
2. Bcr-Abl is transported in core, and utilizes the kinase activity of Bcr-Abl, phosphorylation p73, activates apoptotic signal, thus the foundation of induction CML apoptosis thinking:
When DNA damage, c-Abl enters core and is activated, and is that DNA damage stress-induced apoptosis is necessary, and when lacking the kinase activity of c-Abl or c-Abl, cell is just insensitive to apoptosis induction.Therefore, c-Abl enters be activated c-Abl while being DNA damage of core and kinase activity and activates the prerequisite of apoptotic signal.Bcr-Abl structurally has the effector domain the same with c-Abl, and kinase activity that the more important thing is Bcr-Abl is constitutively activate in cell, and therefore, Bcr-Abl enters in core just can pass through its kinase activity phosphorylation p73, cell death inducing.
3. the Bcr-Abl of CML cell is transported to the strategy in core:
1. nuclear localization signal (NLS) albumen by endochylema to the effect in transhipment in karyon: the albumen in eukaryotic cell need to be by nucleus and cytoplasm to transhipment in karyon by endochylema between the nuclear Pore Complex of barrier nuclear membrane, this process is that the guiding by nuclear localization signal (NLS) occurs.
2. forms of rapamycin analogs movement system (rapamycin analog transport system, RATS): rapamycin (Rapamycin) is a kind of natural micromolecular compound, it is in cell and FKBP albumen (FK506-binding protein, FKBP) in conjunction with forming after rapamycin-FKBP binary complex, to rapamycin target (mammalian traget of rapamycin, mTOR) FRB structural domain (FKBP-rapamycin binding domain, FRB) there is very high affinity and specificity, form FRB-rapamycin-FKBP ternary complex, thereby selective induction the interaction of FRB and FKBP.Therefore, if nuclear localization signal and FRB are merged, under the protein-interacting of rapamycin induction, signal for locating is delivered to FKBP, or with the target protein that FKBP merges, in this way, just can realize the transhipment of albumen.For fear of rapamycin on Normocellular impact, available forms of rapamycin analogs (rapamycin analog) is that AP21967 replaces rapamycin, simultaneously to the FRB modification that suddenlys change, the FRB that AP21967 just only modifies in conjunction with sudden change like this, and not in conjunction with the FRB of intracellular rapamycin target.In sum, forms of rapamycin analogs AP21967 and FKBP, FRB and the nuclear localization signal merging with it have also just formed forms of rapamycin analogs nuclear translocation system (rapamycin analog transport system, RATS), the pyrenoids transhipment realizing by RATS has also obtained application in increasing research.
3. how RATS realizes the target transhipment to Bcr-Abl: the SH2 of Grb2 (Src homology 2, SH2) the Y177 specific binding of structural domain and Bcr-Abl, when AP21967 induction FRB and FKBP interaction, just the nuclear localization signal merging with FRB can be passed to the SH2 merging with FKBP, further pass to Bcr-Abl, thereby Bcr-Abl is transported into core.
4. thereby how exogenous FKBP-SH2 and NLS-FRB fusogenic peptide enter target cell transhipment Bcr-Abl and enter core and activate p73: select Ad5 adenovirus carrier as expression vector, construction expression FKBP-SH2 and with the NLS-FRB fusogenic peptide of nuclear localization signal respectively, adenovirus is infected to CML cell simultaneously, add after AP21967, RATS target transhipment Bcr-Abl enters core, that both can reduce Bcr-Abl protein level in endochylema and mediation thereof causes leukemia signal, can make again to bring into play its kinase activity into the Bcr-Abl of core, phosphorylation p73, activate apoptotic signal, reach the apoptotic object of induction CML.
According to above foundation, carry out actual operation, found successful.
In experimental verification invention effect, for the convenience detecting, add the preceding paragraph aminoacid sequence FLAG label form FN3R at N3R front end, FLAG label is specially: DYKDDDDK; At F2S front end, add the preceding paragraph aminoacid sequence HA label and form HF2S, HA label is specially: YPYDVPDYAVD.
1. the Construction and identification of recombinant adenovirus Ad5-FN3R, Ad5-HF2S
FN3R fragment obtains by overlapping pcr amplification, by molecular cloning method, FN3R fragment is inserted to Shuttle vector pAdTrack-CMV, through bacterium colony PCR screening, double digestion and order-checking, identify, confirm that the plasmid pAdTrack-CMV-FN3R building conforms to the sequence of expection.Adopt substep clone's method, by HA, two sections of FKBP and SH2 insert in pAdTrack-CMV successively, build the plasmid containing HF2S fragment.Through bacterium colony PCR screening, double digestion and order-checking, identify, confirm that the plasmid pAdTrack-CMV-HF2S building conforms to the sequence of expection.Same method builds the plasmid containing sudden change fragment HF2Sm.The skeleton plasmid pAdEasy-1 of shuttle plasmid and adenovirus is recombinated in BJ5183 bacterium, through agarose gel electrophoresis, Pac I enzyme, cut evaluation, filter out adenovirus carrier Ad5-FN3R, Ad5-HF2S, the Ad5-HF2Sm of correct restructuring.By transfection AD-293 cell after adenovirus carrier Ad5-FN3R, Ad5-HF2S, Ad5-HF2Sm linearizing, in AD-293 cell, carry out packing, the amplification of adenovirus, obtain adenovirus Ad5-FN3R, Ad5-HF2S, the Ad5-HF2Sm of high titre.
2.PCR and western blot identify FN3R, HF2S and the expression of HF2Sm in cell
Adenovirus solution, after Proteinase K is processed, carries out pcr amplification as template, each virus object band (A, B in Fig. 1) that all increases to obtain.And take the negative control that Ad5 zero load is template, there is no band.Recombinant adenovirus infects after AD-293 cell and K562 cell, extracts total protein, and Western blot detects the expression of target protein in two kinds of cells, and the unloaded control group of Ad5 does not detect expression (C, D in Fig. 1).
In Fig. 1, A.PCR identifies the expression .M:DL2000 standard of FN3R mRNA, 1,2:FN3R virus liquid,
3: positive control, 4: negative control. in Fig. 1, B.PCR identifies the expression .M:DL2000 standard of HF2S mRNA, 1,6: negative control, 2: the Ad5-HF2S adenovirus of correct restructuring, 3: positive control, 4: the Ad5-HF2Sm adenovirus of correct restructuring, 5: positive control. in Fig. 1, C.Western blot identifies FN3R, HF2S and the expression of HF2Sm in AD-293 cell. in Fig. 1, D.Western blot identifies FN3R, HF2S and the expression of HF2Sm in K562 cell.
3. immunofluorescence detects FN3R, HF2S and the location (referring to Fig. 2) of HF2Sm in K562 cell
With Ad5-FN3R, Ad5-HF2S or Ad5-HF2Sm adenovirus infection K562 cell, MOI is 10
5, 48h collecting cell carries out immunofluorescence experiment, detects FN3R, HF2S and the location of HF2Sm albumen in K562 cell.Result is as shown in Figure 2: FN3R is mainly positioned nucleus, and HF2S, HF2Sm are mainly positioned cytoplasm, conforms to expection.
4. immunofluorescence detection RATS transhipment Bcr-Abl enters core front and back Bcr-Abl and the location of target protein in K562 cell
The K562 cell of inoculation proper density is in Tissue Culture Plate, and with adenovirus Ad5-FN3R and Ad5-HF2S or (Ad5-HF2Sm) coinfection K562 cell, MOI is 10
5.After 12h, add AP21967, after 48h, collecting cell smear, carries out immunofluorescence experiment.After adenovirus Ad5-FN3R and Ad5-HF2S coinfection K562 cell, when not adding AP21967, FKBP can not be in conjunction with FRB, the albumen that the NLS merging with FRB can not pass to FKBP and merge with it, with HA antibody test to be to be positioned at cytoplasmic HF2S, now, Bcr-Abl is still positioned cytoplasm (A in Fig. 3), after adding AP21967, FKBP and FRB interact, the albumen that the NLS merging with FRB passes to FKBP and merges with it, finally pass to Bcr-Abl, with HA antibody test to albumen comprise HF2S and FN3R, mainly be positioned at nucleus, Bcr-Abl is partly transported to nucleus (B in Fig. 3).At Ad5-FN3R and Ad5-HF2Sm coinfection control group, the Sm that NLS can pass to FKBP and merge with it, but because Sm can not be in conjunction with Bcr-Abl, thus with HA antibody test to albumen comprise FN3R and HF2Sm, mainly be positioned at nucleus, Bcr-Abl is still arranged in cytoplasm (Fig. 3 C).Above result confirms that RATS can transport Bcr-Abl and enter core.The effect that enters core due to Bcr-Abl in RATS transhipment K562 cell is strong not, and according to the literature, leptomycin B (LMB) can suppress NLS and go out core, strengthens into nuclear effect.Therefore, we are by adding LMB to strengthen the effect that RATS transhipment Bcr-Abl enters core.Immunofluorescence confirms that independent 0.2nM LMB can not induce Bcr-Abl to enter core (E in Fig. 3), but can significantly strengthen RATS transhipment Bcr-Abl, enters core (D in Fig. 3), and above result confirms that LMB has strengthened Bcr-Abl in RATS transhipment K562 cell and entered core.
5.RATS suppresses K562 cell proliferation
In order to make the LMB of our concentration used not produce significantly impact to the growth of K562 cell, to guarantee that LMB only helps out to RATS, we use different concns (0.2nM, 0.5nM, 1nM, 2nM and 5nM) LMB process K562 cell, 24 and the MTS result of 48h confirm, when LMB concentration is 0.2nM on the growth of K562 cell almost without affecting (Fig. 4).Further with the LMB of 0.2nM and two concentration of 0.5nM, process K562 cell, the 2nd, the LMB that the MTS result of 4,6 days also confirms 0.2nM on the growth of K562 cell without impact (Fig. 5).Therefore the LMB of we selected 0.2nM is follow-up test concentration.As shown in Figure 6, (curve a) is compared with Normal group, RATS has suppressed the growth (curve c) of K562 cell to a certain extent, and under LMB is auxiliary, K562 Growth of Cells is obviously suppressed (curve d), and sudden change control group (curve e) and unloaded control group (curve b) are on the not significant impact of the growth of K562 cell.These results suggest that, RATS can suppress the growth of K562 cell, and 0.2nM LMB has significantly strengthened the inhibitory effects on proliferation of RATS to K562 cell.
6.RATS induction K562 apoptosis
Take MOI as 10
5, Ad5-FN3R and Ad5-HF2S adenovirus coinfection K562 cell, add AP21967 after 12h, add 0.2nM LMB after 24h, collecting cell after 72h, and Wright's staining detects form, the nuclear changing conditions of DAPI staining examine of K562 cell.Normal group (control) is set up in experiment simultaneously; Do not add AP21967 group (RATS
-): after Ad5-FN3R and Ad5-HF2S coinfection, do not add AP21967, all the other process same experimental group; Sudden change control group (RATSm): Ad5-FN3R and Ad5-HF2Sm coinfection K562 cell, all the other processing are identical with experimental group.Wright's staining (Fig. 7) finds that RATS treatment group cell size differs, and endochylema red-purple particle increases, part Vacuole formation, and there is obvious karyopyknosis, cracked in part cell, illustrates that apoptotic cell increases.And Normal group, RATS
-group and RATS
tMgroup, cell is complete, big or small homogeneous, apoptotic cell is rare.This explanation RATS has induced K562 apoptosis.DAPI dyeing (Fig. 8) finds that RATS treatment group nucleus occurs that the apoptosis such as pyknosis, cracked, dissolving change, and counts 1000 nucleus, and apoptosis rate is 22%.And Normal group, RATS
-group and RATSm group, nucleus homogeneous, circle or similar round, accidental pyknosis or cracked nucleus.This further confirms that RATS has induced K562 apoptosis.
We further detect the Activation of caspase 3 with western blot.RATS group caspase 3 is activated, and cuts out the activation fragment of 17kDa; And Normal group does not add Ap21967 group and sudden change control group, all have no caspase activation (Fig. 9).Presentation of results RATS has induced K562 apoptosis by caspase 3.
Beneficial effect:
Verify by experiment system and method for the present invention, can reach and realize induction CML apoptosis, and effect is very good, for the exploitation for the treatment of leukemic research and medicine, has very large researching value.
Accompanying drawing explanation
Fig. 1 is the expression identification figure of FN3R, HF2S and HF2Sm;
Fig. 2 is that immunofluorescence detects FN3R, HF2S and the location map of HF2Sm albumen in K562 cell;
Fig. 3 is that immunofluorescence detection RATS transhipment Bcr-Abl enters core front and back Bcr-Abl and the location map of target protein in K562 cell;
Fig. 4 is the graphic representation that the LMB of different concns affects K562 Growth of Cells;
Fig. 5 is 0.2,0.5nM LMB at different time the graphic representation on the impact of K562 Growth of Cells;
Fig. 6 is that RATS suppresses K562 cell proliferation;
Fig. 7 is that Wright's staining confirms RATS induction K562 apoptosis figure;
Fig. 8 is that DAPI dyeing confirms RATS induction K562 apoptosis figure;
Fig. 9 is the evaluation figure that RATS activates caspase 3;
Figure 10 is for allowing the apoptotic system schematic of chronic myelocytic leukemia (CML).
Embodiment
Embodiment
As shown in figure 10, a kind of apoptotic system of chronic myelocytic leukemia (CML) that allows, is linked together and is formed by the fusogenic peptide F2S that is written into two fusogenic peptide N3R, two compd A P21967 of adenovirus and is written into adenovirus;
Described fusogenic peptide N3R is that 3 sections of NLS and FRB connect to form, and described fusogenic peptide F2S is that 2 sections of FKBP and SH2 connect to form,
One section of FKBP is combined with one section of FRB by a compd A P21967; A fusogenic peptide F2S passes through compd A P21967 simultaneously in conjunction with two fusogenic peptide N3R;
The aminoacid sequence of described fusogenic peptide N3R is:
PKKKRKVPKKKRKVPKKKRKVELIRVAILWHEMWHEGLEEASRLYFGERNVKGMFEVLEPLHAMMERGPQTLKETSFNQAYGRDLMEAQEWCRKYMKSGNVKDLLQAWDLYYHVFRRISKQ；
The nucleotide sequence of described fusogenic peptide N3R is as shown in SEQ ID No.1;
The aminoacid sequence of described fusogenic peptide F2S is:
MGVQVETISPGDGRTFPKRGQTCVVHYTGMLEDGKKFDSSRDRNKPFKFMLGKQEVIRGWEEGVAQMSVGQRAKLTISPDYAYGATGHPGIIPPHATLVFDVELLKLEAAAMGVQVETISPGDGRTFPKRGQTCVVHYTGMLEDGKKFDSSRDRNKPFKFMLGKQEVIRGWEEGVAQMSVGQRAKLTISPDYAYGATGHPGIIPPHATLVFDVELLKLEGTLEWFFGKIPRAKAEEMLSKQRHDGAFLIRESESAPGDFSLSVKFGNDVQHFKVLRDGAGKYFLWVVKFNSLNELVDYHRSTSVSRNQQIFLRDIE；
The nucleotide sequence of described fusogenic peptide F2S is as shown in SEQIDNo.2.
Specifically allow the method for chronic myeloid leukemia cell apoptosis:
The fusogenic peptide N3R of adenovirus will be written into, compd A P21967 and the fusogenic peptide F2S that is written into adenovirus import in chronic myeloid leukemia cell, FRB is combined with compd A P21967, this compd A P21967 is combined with FKBP again, form FRB-AP21967-FKBP ternary complex, N3R and F2S are linked together and formed the system of chronic myeloid leukemia cell apoptosis of allowing, SH2 can be in conjunction with Bcr-Abl cancer protein simultaneously, FRB passes to Bcr-Abl cancer protein by signal for locating, Bcr-Abl cancer protein is transported into core, by the tyrosine kinase activity phosphorylation activation p73 of Bcr-Abl cancer protein, induction CML apoptosis.
Sequence table
<110> Medical University Of Chongqing
Mono-kind of <120> allows system and the method thereof of chronic myeloid leukemia cell apoptosis
<160> 2
<210> 1
<211> 353
<212> DNA
<213> artificial sequence
<220>
<400>CCTAAGAAGA AGAGGAAGGT TCCTAAGAAG
AAGAGGAAGG TTCCTAAGAA GAAGAGGAAG GTTGAGCTGA
TCCGAGTGGC CATGAGATGT GGCATGAAGG CCTGGAAGAG
GCATCTCGTT TGTACTTTGG GGAAAGGAAC GTGAAAGGCA
TGTTTGAGGT GCTGGAGCCC TTGCATGCTA TGATGGAACG
GGGCCCCCAG ACTCTGAAGG AAACATCCTT TAATCAGGCC
TATGGTCGAG ATTTAATGGA GGCCCAAGAG TGGTGCAGGA
AGTACATGAA ATCAGGGAAT GTCAAGGACC TCCTCCAAGC
CTGGGACCTC TATTATCATG TGTTCCGACG AATCTCAAAG
CAG
<210> 2
<211> 927
<212> DNA
<213> artificial sequence
<220>
<400> ATGGGAGTGC AGGTGGAAAC CATCTCCCCA GGAGACGGGC GCACCTTCCC CAAGCGCGGC CAGACCTGCG TGGTGCACTA
CACCGGGATG CTTGAAGATG GAAAGAAATT TGATTCCTCC
CGGGACAGAA ACAAGCCCTT TAAGTTTATG CTAGGCAAGC
AGGAGGTGAT CCGAGGCTGG GAAGAAGGGG TTGCCCAGAT
GAGTGTGGGT CAGAGAGCCA AACTGACTAT ATCTCCAGAT
TATGCCTATG GTGCCACTGG GCACCCAGGC ATCATCCCAC
CACATGCCAC TCTCGTCTTC GATGTGGAGC TTCTAAAACT
GGAAATGGGA GTGCAGGTGG AAACCATCTC CCCAGGAGAC
GGGCGCACCT TCCCCAAGCG CGGCCAGACC TGCGTGGTGC
ACTACACCGG GATGCTTGAA GATGGAAAGA AATTTGATTC CTCCCGGGAC AGAAACAAGC CCTTTAAGTT TATGCTAGGC AAGCAGGAGG TGATCCGAGG CTGGGAAGAA GGGGTTGCCC AGATGAGTGT GGGTCAGAGA GCCAAACTGA CTATATCTCC AGATTATGCC TATGGTGCCA CTGGGCACCC AGGCATCATC CCACCACATG CCACTCTCGT CTTCGATGTG GAGCTTCTAA AACTGGAATG GTTTTTTGGC AAAATCCCCA GAGCCAAGGC AGAAGAAATG CTTAGCAAAC AGCGGCACGA TGGGGCCTTT CTTATCCGAG AGAGTGAGAG CGCTCCTGGG GACTTCTCCC TCTCTGTCAA GTTTGGAAAC GATGTGCAGC ACTTCAAGGT GCTCCGAGAT GGAGCCGGGA AGTACTTCCT CTGGGTGGTG AAGTTCAATT CTTTGAATGA GCTGGTGGAT TATCACAGAT CTACATCTGT CTCCAGAAAC CAGCAGATAT TCCTGCGGGA CATAGAA
Claims (2)
1. allow the system of chronic myeloid leukemia cell apoptosis, it is characterized in that: by the fusogenic peptide F2S that is written into two fusogenic peptide N3R, two compd A P21967 of adenovirus and is written into adenovirus, link together and form;
Described fusogenic peptide N3R is that 3 sections of NLS and FRB connect to form, and described fusogenic peptide F2S is that 2 sections of FKBP and SH2 connect to form,
One section of FKBP is combined with one section of FRB by a compd A P21967; A fusogenic peptide F2S passes through compd A P21967 simultaneously in conjunction with two fusogenic peptide N3R;
The aminoacid sequence of described fusogenic peptide N3R is:
PKKKRKVPKKKRKVPKKKRKVELIRVAILWHEMWHEGLEEASRLYFGERNVKGMFEVLEPLHAMMERGPQTLKETSFNQAYGRDLMEAQEWCRKYMKSGNVKDLLQAWDLYYHVFRRISKQ；
The nucleotide sequence of described fusogenic peptide N3R is as shown in SEQ ID No.1;
The aminoacid sequence of described fusogenic peptide F2S is:
MGVQVETISPGDGRTFPKRGQTCVVHYTGMLEDGKKFDSSRDRNKPFKFMLGKQEVIRGWEEGVAQMSVGQRAKLTISPDYAYGATGHPGIIPPHATLVFDVELLKLEAAAMGVQVETISPGDGRTFPKRGQTCVVHYTGMLEDGKKFDSSRDRNKPFKFMLGKQEVIRGWEEGVAQMSVGQRAKLTISPDYAYGATGHPGIIPPHATLVFDVELLKLEGTLEWFFGKIPRAKAEEMLSKQRHDGAFLIRESESAPGDFSLSVKFGNDVQHFKVLRDGAGKYFLWVVKFNSLNELVDYHRSTSVSRNQQIFLRDIE；
The nucleotide sequence of described fusogenic peptide F2S is as shown in SEQ ID No.2.
2. a kind of system that allows chronic myeloid leukemia cell apoptosis according to claim 1, is characterized in that: the adenovirus that described fusogenic peptide N3R and F2S are written into is Ad5 adenovirus.
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| CN106987599B (en) * | 2017-03-28 | 2021-06-11 | 重庆医科大学 | Zinc finger nuclease for inhibiting expression of human bcr-abl fusion gene or causing loss of function of human bcr-abl gene and application thereof |
| CN112575035B (en) * | 2020-12-09 | 2022-11-29 | 贵州医科大学 | Carrier system for inducing apoptosis |
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