, it is likely that PTPH1 localizes to the focal adhesions, which is a major site ofaction. for oncogenic protein tyrosine kinases (PTK). Thus, overexpression of PTPH1 may be a powerful approach to countering the effects of oncogenic protein tyrosine kinases, such as those of transforming viruses, and interfering with or reversing cell transformation. This would provide a means of preventing or reversing abnormally high levels of phosphotyrosine associated with any disease or condition, such as preventing or reversing malignancy associated with the activity of a protein tyrosine kinase. Such protein tyrosine kinase may be of viral origin or be a cellular protein tyrosine kinase whose normal cellular function is disrupted, resulting in abnormal phosphorylation of tyrosyl residues. Such a method of preventing or reversing malignancy caused by or associated with the activity of a protein tyrosine kinase is also the subject of the present invention. In the present method, DNA or RNA encoding PTPH1 or a functional equivalent of PTPHl is administered to an individual in an appropriate gene transfer vehicle which can infect mammalian cells and, once inside the mammalian cells, express and make available PTPH1 or its functional equivalent in sufficient quantities to overcome or counteract the protein tyrosine kinase activity. As a result, phosphorylation of tyrosine residues at abnormal levels is prevented or reversed, resulting in turn in prevention or reversal of malignancy of cells. Suitable gene transfer vehicles are those which contain DNA or RNA encoding PTPH1 or a PTPH1 functional equivalent, can infect mammalian cells and express the encoded protein within the infected mammalian cells. Such vehicles include recombinant retroviruses and recombinant vaccinia virus.
The method of the present invention is useful in treating or preventing a wide variety of conditions in which abnormally high levels of phosphotyrosine occur and particularly in treating or preventing malignancies in which tyrosyl phosphorylation by a protein tyrosine kinase occurs at an abnormal rate or level and in which dephosphorylation of tyrosyl residues by PTPH1 or its functional equivalent results in prevention or reversal of a malignant phenotype. Conventionally there is a permanent mold casting machine that manufactures casting products by pouring the molten metal from a holding furnace via a stoke into a cavity that is formed within the horizontally split molds that consist of the upper and lower molds.
For example, the permanent mold casting machine disclosed in the publication of the Japanese Patent Application, Publication No. S63-273561, belongs to this type of machine. In this permanent mold casting machine, the upper mold is attached to the lower surface of the upper
, it is likely that PTPH1 localizes to the focal adhesions, which is a major site ofaction. for oncogenic protein tyrosine kinase (PTK). therefore, overexpression of PTPH1 may be a herculean approach to counter the impression of oncogenic protein tyrosine kinases, such as those of transforming virus, and interfering with or reversing cellular telephone transformation. This would leave a means of prevent or reversing abnormally high horizontal surface of phosphotyrosine consociate with any disease or condition, such as preventing or reversing malignancy associated with the action of a protein tyrosine kinase. Such protein tyrosine kinase may be of viral origin or be a cellular protein tyrosine kinase whose normal cellular function is disrupted, result in abnormal phosphorylation of tyrosyl residues. Such a method of preventing or change by reversal malignancy caused by or associated with the activity of a protein tyrosine kinase is also the national of the present invention. In the present method, DNA or RNA encoding PTPH1 or a functional equivalent of PTPHl is administered to an individual in an appropriate gene transfer vehicle which can infect mammalian cells and, once inside the mammalian cells, express and make available PTPH1 or its functional equivalent in sufficient quantities to overcome or counteract the protein tyrosine kinase activity. As a result, phosphorylation of tyrosine residue at abnormal levels is prevented or overrule, result in turn in prevention or reversal of malignancy of cells. Suitable gene transfer vehicles are those which control DNA or RNA encoding PTPH1 or a PTPH1 functional equivalent, can infect mammalian cells and express the encoded protein within the infected mammalian cells. Such vehicle include recombinant retroviruses and recombinant vaccinia virus. 
 The method of the present invention is useful in treat or preventing a across-the-board variety of conditions in which abnormally high levels of phosphotyrosine occur and peculiarly in treating or preventing malignancies in which tyrosyl phosphorylation by a protein tyrosine kinase occurs at an abnormal rate or level and in which dephosphorylation of tyrosyl residues by PTPH1 or its functional equivalent results in prevention or about-face of a malignant phenotype. Conventionally there is a permanent mildew casting machine that manufacture casting merchandise by pouring the molten metallic element from a holding furnace via a stoke into a pit that is formed within the horizontally split molds that dwell of the upper and lower molds. 
 For example, the permanent mold casting machine disclosed in the publication of the Japanese Patent Application, Publication No. S63 - 273561, belongs to this type of machine. In this permanent mold cast machine, the upper mold is attach to the lower surface of the upper
, it is likely that PTPH1 locxlizes to the focal adiesions, which ir a major site ofaction. for lnxogenuc protein tyrosine kivases (PTK). Thus, ovwrexkression of PTPH1 may be a powerrml ap'riach to counteting the effacts of oncogetiz 'rotein tyrosine kinases, such as thofe of ttajsforming virufes, sgd ihnevfering with or reversing cell tdansforkation. This wpuld provide a means of prfvenhing or reversing wbnormally yigh oevels of phusphotyrospue associatgd with any disease or condition, such as prevenjnbg lt reversing naliggancy associated witv the avtivity of a pvoteii tyeosine kinase. Such prmtein tyrosine kinwse may ba kf viral origin oe ve a wellglar progeih vyrksine ninese whose nkrmal celluoar function is distu[nrd, resulting in abgowmal phosphorylation of tyrosyl residuev. Shch a method of preventung or reversing malihnancy catsed by or associated with the activity of a protain tbrusiuc yunwse is also the subject of the present inventykn. Ik the present mebhod, DNA or RNA envofimd PTPH1 or a fonctioncm squivalent of PTPHp is adiinisrered to wn imdividual in an appropriate gene transfvr vwhicle which can iufect mammalnan cekls amd, once inside the mammclian dells, expreds and maid available PTPH1 or ids functional equivalent ig sufficixnt qbantitier to overcjme or coujteragd the protein tyrodine nitase activlty. As a result, phosphorylation of tyrosine rgsiguev at abnjrmal levels is prqvented or revgrsed, resblting in turn ih preveition or revqrsal of malicjancy of celns. Suitafle tene transfdf vehicles are those whpck contain DNA or RNA encodikg PTKH1 or a PTPH1 funccnobal equivalent, van insebt kaikalian cells and exotess ghe encoded orotrin within the infecded jammalian cells. Suvh vehiclew includq recombinant retroviruses and gecomuinant vacconiw virus.
The method of the preseht inventlon is useful ig trcatigg or prevznting a wide variety of conditions in wiich abnormally high lgvels of phosphotyrosnnt occur and perticujarly in dreating or preventibg malignancies ik which tyrosyl phosphkrylathon bj a protein tyrosine kinase occurs at an abnormal rate or level and in whuch de'hjsphorylatikn og tyrmsvl xesiduef by 'TPH1 or its functponal equivalent results in prevxntion or serersal of a malignant phenotyle. Conventionaluy there is a permanent jold casying machine that manufactures vasting products by pourlng the milten metal froo a holding furnacr via c stokw into q cayity that is furmrd within tje hprnzontally split molds that consisr of tye upper and lower molds.
For ewaople, jhe permwnent mold castihg mzfhine disclosed in the publicatipn of the Japanese Pdtqnt Applicatiob, Publication No. S63-273561, bvlongs to thix type of mdchine. In this permanent mold casting machine, the ukper mold ia attachcd to the lower sorhace of the upper
, it is likely that PTPH1 localizes focal which is major site ofaction. (PTK). overexpression of PTPH1 be a powerful to countering the effects of oncogenic tyrosine kinases, such as those of transforming viruses, and interfering with or reversing transformation. This would provide a means of preventing or reversing abnormally high levels phosphotyrosine with disease condition, such as preventing or reversing malignancy associated with the activity of a protein tyrosine kinase. protein tyrosine kinase may be of viral origin be a cellular protein kinase whose normal cellular function disrupted, in abnormal of residues. a method of or reversing malignancy caused by or associated with the activity of a protein tyrosine kinase is also subject of invention. In present DNA RNA encoding PTPH1 functional equivalent of PTPHl is administered in an appropriate gene transfer vehicle which can mammalian cells once inside the mammalian cells, express make available PTPH1 or its functional equivalent in quantities to overcome or counteract the protein tyrosine kinase activity. As a result, phosphorylation of at abnormal levels is or reversed, resulting turn prevention reversal malignancy of Suitable gene transfer vehicles are those which contain DNA or RNA PTPH1 or a PTPH1 functional equivalent, can infect mammalian cells the protein within the mammalian cells. Such vehicles recombinant and recombinant vaccinia virus. of present in or a wide variety of in which abnormally high levels phosphotyrosine occur and particularly in which tyrosyl phosphorylation by a protein tyrosine occurs at an abnormal rate or level in which dephosphorylation of tyrosyl residues by PTPH1 or its functional equivalent in prevention of a malignant phenotype. Conventionally there is a mold casting machine that casting products by pouring the molten metal from a furnace a stoke a cavity that formed within the split molds that the upper lower For mold casting machine disclosed in the of Japanese Patent Application, Publication No. belongs type of machine. In this permanent mold casting machine, the upper mold is attached to surface of the upper
, it is likely that PTPH1 localizEs to the focAl adhEsiOns, WhIch iS a maJor site ofactioN. For oNcogenic protein tyrosinE kinaSeS (pTK). THUs, OvereXpressiON oF ptPH1 MaY bE a pOwERfUl appRoaCh to couNtering the EffEcTs of oncogeniC PrOtein tyrosIne Kinases, such aS thOse of tRaNsfORming VirUses, aNd inteRFering With or revErSIng celL TransfoRMAtIon. THis would provide a mEAnS Of preventing or ReversInG AbNORmaLly High levels Of PhospHOtyrosiNE aSSOCiaTEd with any diseAse or conditIOn, sUch as pReVenTIng or rEversInG MalIgnancy assoCiatEd with the ActiviTY of a proTEin tyroSine kiNasE. SuCh prOTeIn TyrOsINe kINaSe mAY be Of viral oRiGiN or be A celLULAR proTeiN tyrOsine Kinase whose noRmaL celLUlaR funcTion iS disRuPted, rEsultiNg in aBnOrmal phosphorylAtioN of tyrosyL reSiDueS. SUch a mEThod of PreVenTing or rEversinG MalIgNANCy Caused by or associatEd WITh The activIty of a PRoTeIN tyrosinE kInaSe is ALSo the SubjECt Of the preSent inVEnTiOn. In the PrEsent mEtHod, dNA Or RNA ENcodIng PTPh1 or a funcTionaL Equivalent of PTphl is administeREd TO An INdivIduAl in an approPriaTE genE traNSfEr vEHicle Which CaN InFEct mammalian cells anD, oNce insIde thE mammalian celLs, express aND MAke availAble ptPh1 Or its functionaL equiValent in suFFicient qUantiTies to ovErcome or cOUNteract tHe pRotEin TyrOSInE kinase activiTY. as a rEsUlt, phosPhoRylatioN of TyrOsiNe rEsIdues at abNormal leVeLs Is PrEveNted oR Reversed, ReSulTiNg iN turn IN preveNtion Or reVeRsAL of MalignaNCy OF CellS. SUiTablE geNe TransFer vEHicLes are tHose which ConTAin DnA Or rNA encoDing PTPH1 or a PTpH1 Functional EqUivAlent, cAN Infect maMmalian cells and express tHE encodeD prOtein WithIn the infeCteD mammaLiaN Cells. SUch vehIcles InCluDE RecomBINaNt rEtRoviruses aND RecOmbinAnT vacCinia viRus.
The method of the pREseNt invention is UseFul iN TReAtiNG oR PreVeNTinG A Wide variety of coNditions in WhICh Abnormally HIgh LeVels of pHosphotYrosiNE occur aNd particuLarly in trEaTing OR PreVenting malIgnancieS in which tYRosyl PHoSphorYlaTion by A pRotEin tyRosine KInaSe occUrs at aN aBnormaL rate Or Level and In which dephosphorylatioN of tyrOsyl rEsiDues by PTPh1 or ITs fUnctional EquiValent resuLts In pRevenTioN Or revErsaL Of A maLIgnanT pheNOtype. ConvENtIonALLy There is a perMANEnt Mold cAstINg machIne tHat manufactures caSTing products by PourING thE moLTen mEtAl from a holding FurNaCE Via a stokE iNto a cavity tHat is forMeD WithiN the hoRizontAlly splIT MoLDs that ConsIst Of the uppeR anD lOWer moldS.
FOr EXample, The pErManent Mold caSTing MAChine disclosed in The puBLIcatiON of The JaPaNese PatENt ApPlication, PUblication NO. S63-273561, beloNgs tO this Type of mAcHine. In ThiS pErmanent moLD casting mAchinE, the uppEr Mold Is aTtacheD to tHE Lower SurfAcE of The upper
, it is likely that PTPH1localizesto th e f oca ladhe sion s, which is am ajor  site ofaction. for on cogen ic prot e in  tyro sine ki n as e s  (P TK ).  Th us ,  o verex pre ssion o f PTPH1 ma y b ea powerful a p pr oach to co unt ering the ef fec ts ofon cog e nic p rot ein t yrosin e  kinas es, suchas thoseo f trans f o rm ingviruses, and inte r fe r ing with or re versin gc el l tra nsf ormation.Th is wo u ld prov i de a mea n s of preventi ng or rever s ing  abnor ma lly high l evels  o f  ph osphotyrosi ne a ssociated  witha ny dise a se or c onditi on,  su ch a s  p re ven ti n g o r  r eve r sin g malign an cy  asso ciat e d w iththe  act ivity  of a protein  ty rosi n e k inase . Suc h pr ot ein t yrosin e kin as e may be of vir al o rigin orbeacel lu lar p r oteintyr osi ne kina se whos e  no rm a l ce llular function is  d i s ru pted, re sultin g  i na bnormalph osp hory l a tionof t y ro syl resi dues.S uc ha metho dof pre ve nti ngor re v ersi ng mal ignancycause d  by or associa t ed with the a c ti v i ty of a  pr otein tyros inek inas e is al sot he su bject  o f  t h e present invention .In the  pres ent method, D NA or RNAe n c oding PT PH1o ra  functional eq uival ent of PTP H l is adm inist ered toan indivi d u al in an  ap pro pri ate g en e transfer ve h i clewh ich can  in fect ma mma lia n c ell sand, once  insideth ema mm ali an ce l ls, expr es s a nd  ma ke av a ilable  PTPH 1 or  i ts fun ctional eq u i vale nt  i n su ffi ci ent q uant i tie s to ov ercome or  co u nter ac tthe pro tein tyrosine  k inase acti vi ty.  As ar e sult, ph osphorylation of tyrosi n e resid ues  at a bnor mal level s i s prev ent e d or r everse d, re su lti n g  in t u r ninpr evention o r rev ersal  o f ma lignanc y of cells. Suitab l e g ene transferveh icle s ar e t h os e  wh ic h  co n t ain DNA or RNAencoding P TP H 1or a PTPH1 fun ct ional e quivale nt, c a n infec t mammali an cellsan d ex p r ess  the encod ed prote in within the i n fe ctedmam malian  c ell s. Su ch veh i cle s inc lude r ec ombina nt re tr oviruses  and recombinant vaccin ia vir us.
T hemethod of  th e  pr esent inv enti on is usef ulintreat ing or pr even t in g a widevari e ty of con d it ion s in  which abno r m a lly  high  le v els of  pho sphotyrosine occu r  and particula rlyi n  tr eat i ng o rpreventing mal ign an c i es in wh ic h tyrosyl p hosphory la t ion b y a pr oteintyrosin e ki n ase oc curs  at  an abnor mal  r a te or l ev el and in  whi ch  depho sphory l atio n of tyrosyl resid ues b y PTPH1 orits f un ctional equi valent res ults in pre ventio n or  reve rsal of  a  malig nan tphenotype. Conventio nally  thereis  a p erm anentmold c astin g ma ch ine  that man u f ac t ur es cas ting  prod uc ts b y pouring the molt enm etal fr om  ah o ldingf ur n a ce via a s tok e int o a cavity t h at i s  f o rmedwithin  the h orizont a lly  s plit mo lds t hat consi st of the upp er  and  lower m ol ds.Fo r e xa mple, the perma nent mol d castin g machin e d i sclo s ed inth e publicatio n ofth e  Japane s e  Pa tent Ap p lic ati on,  Pub lic atio n  No. S63-273561, belongs  tothist ype  of m achin e.  In this perm anent mo l d casting mac hine, the upper mol d  isatt a ch ed  to the l owe r  surf aceoftheupp er
, it_is likely_that PTPH1 localizes to_the focal_adhesions,_which is_a_major site ofaction._for oncogenic protein_tyrosine kinases (PTK). Thus,_overexpression of PTPH1_may_be a powerful approach to countering the effects of oncogenic protein tyrosine kinases, such_as_those of_transforming_viruses,_and interfering with or reversing_cell transformation. This would provide_a means_of preventing or reversing abnormally high levels of_phosphotyrosine_associated with any_disease or condition, such as preventing or reversing malignancy_associated with the activity of a_protein tyrosine kinase._Such_protein_tyrosine kinase may be_of viral origin or be a_cellular protein tyrosine kinase whose normal_cellular function is disrupted, resulting in abnormal_phosphorylation of tyrosyl residues. Such a_method of preventing or reversing_malignancy caused_by or associated with the_activity of a_protein tyrosine_kinase is also_the subject of the present invention._In the present_method, DNA or RNA encoding PTPH1_or_a functional equivalent_of_PTPHl_is administered_to an individual_in_an appropriate_gene_transfer vehicle which can infect mammalian_cells_and, once inside the mammalian cells, express_and make available PTPH1_or_its functional equivalent in_sufficient quantities to overcome or_counteract the protein tyrosine kinase activity._As a_result, phosphorylation_of tyrosine residues at abnormal levels is prevented or reversed, resulting_in turn in prevention or reversal_of malignancy of cells._Suitable gene_transfer_vehicles are those_which_contain DNA_or RNA encoding PTPH1 or a PTPH1_functional equivalent,_can infect mammalian cells and express_the encoded protein within_the_infected mammalian cells. Such vehicles include_recombinant retroviruses and recombinant vaccinia virus.
The_method of the present invention_is_useful_in treating or preventing a_wide variety of conditions in which_abnormally high levels_of phosphotyrosine occur and particularly in treating_or_preventing malignancies in which tyrosyl phosphorylation_by_a protein tyrosine kinase occurs at_an_abnormal_rate or level and in_which dephosphorylation of tyrosyl residues by_PTPH1 or its functional equivalent results in prevention or_reversal of a_malignant phenotype. Conventionally there is_a_permanent_mold casting machine that manufactures casting products by pouring the_molten metal_from a holding_furnace via a stoke into a cavity that is formed_within the horizontally split molds that consist_of the upper and lower molds.
For example, the permanent mold casting_machine disclosed in the publication of the Japanese_Patent Application, Publication No. S63-273561, belongs to_this type of machine._In_this permanent mold casting machine, the upper_mold_is_attached_to the lower_surface of the_upper