I ns t i t ut e of DNA Medi ci ne
Depar t ment of Mol ecul ar Genet i cs
Hisashi Yamada,Professor and Director Takeshi Kawano,Assistant Professor Masaharu Akiyama,Assistant Professor
Gener al Summar y
Ca nc e r i s t he l e a di ng c a us e of de a t h i n J a pa n. Mor e t ha n 3 0 0 , 0 0 0 pe opl e di e of c a nc e r e v e r y y e a r . Wi t h t he g oa l of c onque r i ng c a nc e r ,a s t a t e a nt i c a nc e r pol i c y wa s e s t a b- l i s he d out i n 2 0 0 7 . Unde r s uc h a s i t ua t i on,we a r e s t udy i ng t o de v e l op i nnov a t i v e t he r a pe ut i c me t hods .
Res ear ch Act i v i t i es
Exp l o r i ng t he e t i o l o g y o f human l e uke mi a
Two g r oups of g e ne s a r e i nv ol v e d i n t he pa t hog e ne s i s of l e uke mi a . One g r oup of g e ne s r e g ul a t e s t he g r owt h of he ma t opoi e t i c c e l l s ,a nd t he ot he r c ont r ol s t he di f f e r e nt i a t i on of c e l l s . The s e g e ne s c o- ope r a t e t o de v e l op l e uke mi a s . Bot h me g a ka r y oc y t i c a nd e r y t h- r oi d l e uke mi a s a r e t houg ht t o or i g i na t e f r om me g a ka r y oe r y t hr oi d pr og e ni t or c e l l s ,but t he c l i ni c a l c ha r a c t e r i s t i c s of t he l e uke mi a s di f f e r ma r ke dl y . Mor e ov e r ,t he mol e c ul a r me c ha ni s m of l i ne a g e s hi f t i ng r e ma i ns l a r g e l y unc l e a r . We r e c e nt l y e s t a bl i s he d a me g a ka r y oe r y t hr oi d l e uke mi a c e l l l i ne ,J AS- R,whos e c e l l s s how a l i ne a g e s hi f t de pe nd- i ng on c ul t ur e c ondi t i ons . The i nt e r a c t i on be t we e n f i br one c t i n a nd i nt e g r i n e l i c i t s t he me g a ka r y oc y t i c phe not y pe a nd l e a ds t o t he l os s of e r y t hr oi d c ha r a c t e r i s t i c s i n J AS- R c e l l s . Ex pr e s s i on pr of i l i ng a na l y s i s r e v e a l e d t ha t s e v e r a l t r a ns c r i pt i on f a c t or s c ha ng e d dur i ng l i ne a g e s hi f t i ng . Of t he s e g e ne s ,FLI 1 wa s c ons i de r e d t o be r e s pons i bl e f or t he e x pr e s s i on of t he me g a ka r y oc y t i c phe not y pe . The s e r e s ul t s a r e us e f ul f or unde r s t a ndi ng nor ma l he ma t opoi e s i s a nd t he t r e a t me nt of l e uke mi a .
Phar mac o l o g y o f ant i c anc e r dr ug s
Se v e r a l l i ne s of e v i de nc e s de mons t r a t e t ha t t e l ome r a s e i s a pr omi s i ng mol e c ul a r t a r g e t f or c a nc e r t he r a py .5 , 1 0 , 1 5 , 2 0 - Te t r a - ( N- me t hy l - 4 - py r i dy l ) por phy r i n( TMPy P4 )i s a c om- pound t ha t bi nds t o t e l ome r e DNA s t a bl y a nd t i g ht l y a nd bl oc ks t e l ome r a s e a c t i v i t y i n v i t r o . Thus ,we s t udi e d t he a nt i c a nc e r a c t i v i t y of TMPy P4 us i ng K5 6 2 l e uke mi c c e l l s a nd f ound t ha t TMPy P4 di r e c t l y i nhi bi t s t he g r owt h of K5 6 2 c e l l s . We a l s o s t udi e d whe t he r TMPy P4 f unc t i ons a s a n a nt i c a nc e r a g e nt f or ot he r c a nc e r c e l l s . Two r e t i no- bl a s t oma c e l l l i ne s ,Y7 9 a nd WERI - Rb1 , we r e s t udi e d. Apopt os i s wa s i nduc e d i n bot h c e l l l i ne s by s hor t - t e r m e x pos ur e t o TMPy P4 . Thi s a popt os i s wa s a s s oc i a t e d wi t h t he phos phor y l a t i on of P5 3 a nd t he a c t i v a t i on of mi t og e n- a c t i v a t e d pr ot e i n ki na s e . Fur t he r mor e ,pr e t r e a t me nt of Y7 9 c e l l s wi t h TMPy P4 i nc r e a s e d r a di a t i on- i nduc e d c e l l de a t h. The s e f i ndi ng s s how t ha t TMPy P4 i s a pot e nt i a l a nt i c a nc e r a g e nt a nd ma y be a ppl i c a bl e f or s ome pa t i e nt s wi t h r e t i nobl a s t oma who r e qui r e r a di a t i on t he r a py .
167 Research Activities 2007 The Jikei University School of Medicine
Publications
Suzuki H,Arakawa Y,Ito M,Saito S,Takeda N, Yamada H, Horiguchi-Yamada J.MLF1- interacting protein is mainly localized in nu- cleolus through N-terminal bipartite nuclear localization signal.Anticancer Res 2007;27:
1423‑30.
Yamada H,Sekikawa T,Iwase S,Arakawa Y, Suzuki H,Agawa M,Akiyama M,Takeda N, Horiguchi-Yamada J.Segregation of megakar- yocytic or erythroid cells from a megakaryocytic leukemia cell line(JAS-R)by adhesion during culture.Leuk Res 2007;31:1537‑43.
Kobayashi K,Shiba A,Yamada H,Ishibashi Y, Nakayama R,Toriumi Y,Mitsumori N,Kashiwagi H,Yanaga K.Frequent splicing aberration of the base excision repair gene hMYH in human gastric cancer.Anticancer Res 2008;28:215‑ 22.
Yamada H,Sekikawa T,Agawa M,Iwase S, Suzuki H,Horiguchi-Yamada J. Adhesion to fibronectin induces megakaryocytic differentia-
tion of JAS-REN cells.Anticancer Res 2008;
28:261‑6.
Mikami-Terao Y,Akiyama M,Yuza Y,Yanagisawa T,Yamada O,Yamada H.Antitumor activity of G-quadruplex-interacting agent TMPyP4 in K562 leukemic cells.Cancer Lett 2008;261:226‑34.
Kashima T,Rao N,David CJ,anley JL (Columbia Univ).hnRNP A1 functions with specificity in repression of SMN2 exon 7 splicing.
Hum Mol Genet 2007;16:3149‑59.
Kawano T,Ito M,Raina D,Wu Z,Rosenblatt J, Avigan D,Stone R,Kufe D (Harvard Univ). MUC1 oncoprotein regul ates Bcr-Abl stability and pathogenesis in chronic myelogenous leuke- mia cells.Cancer Res 2007;67:11576‑84.
Ramasamy S,Durasamy S,Barbashov S, Kawano T,Kharbanda S,Kufe D (Harvard Univ). The MUC1 and galectin-3 oncoproteins function in a microRNA-dependent regulatory loop.Mol Cell 2007;27:992‑1004.
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Research Activities 2007 The Jikei University School of Medicine
