12
致膌膑腬膕膀膙膟膦臎臖 Vol. 36, pp. 7182, 2008 腌腉腅腇腎腊腍腈腄腆腀腋腏腒腂腁腃腐腑 腇腄 腆腇 腇腃 腂腂 腈腊 腉腅 : 20 4 7 腓腐腘腒 腇腫臚腨腖膐膅腰腺膕膈膔腼腬腶腀膎 腃腁腄腂 2 腖腝腈腛膸膯腝臲膠腆腥腇腫臚腾腖腛臮腪腙腋腗腂腧1 腖腞 cDNA 膌腮腱膔 腬膓腮腜腤腧膘膻膈膔膆腭腀膒腪腞腏腢腙腎 腹膄腖膡臵腪腂腓腇腫腝膼膝腘腁腦腣腃膚 腖腞至腈腜臒膮膡臵腝臲膠腆腥膢腍腨腓腨腖腘腁腧臉腛膘臒膗自腪膴腜臘 膗腛腕腓至腖腛臱腪腐腧腪腋腝臤臅腘腁 腧腇腫腪腒腝至腖腛臱腆腥腮腰腎腗腨腖 臋腘腒腝臞腪腖腊臚腌腨腆腥腝腇腫臚腝腴腸膕腹腀腾腛腴腵腜腛腕腗腂腊腣腝腙臔腩腨 膻臌臨膛腁腧腂腞臨臕膺膣腜腁腧腨腖腽臋腞腠腙腫腚腇膑膕臏膝臃腐腛腩腔腰 膀腀腵腪腨腖腙腐腧腣腝腘腁腧 1腰膀腀腵膸 膯腝臑腞膽腊腌腩腖腨腖腘腁腧 ErbB2HER2 腇腰膀腀腵腘腁腧腌腙腇膹腍腨腓腝腞 20 臻腘腁腧腌腨腜腎腗膐膅腰腺膕膈膔腼腬 腶腀膎膳腝腆腉腪膖腧膐膅腰腺膕膑腯腀腵腝腞臹腊腌腩腖腛膏腺腀膆腘腁腧 RING 膆腭膕 腯腀腇膐膅腰腺膕膑腯腀腵腘腁腧腌腙腇腩腆腕腓腝 1999 1腠腙腫腚腝膐膅腰腺膕膑腯腀腵腞腒 腝膾腜膹腍腨腗腂腧腶腜腜腞腰膀腀腵腤腦腞 腧腆腜腊腝臠腝膐膅腰腺膕膑腯腀腵腇臌腐腧 腌腙腆腥膐膅腰腺膕膝臣臬腇臊腜膠腓腐膧腞自腜臉腆腖臦臈膱腌腝膳腨腖 腙腎腓腇腫臚膈腽臋腇膢腍腨腗腂腧 1腽腻 膈膃腻腸腀腘腁腧膈膔腼腬腶腀膎膥臋腝膊膒腼腷 膍膇 bortezomib: VelcadePS-341腆腣臱臆臯 臡腜腔腸腛膿膠腪腢腓腌腙腆腥臇膾膐膅腰腺 膈膔腼腬腶腀膎膳腨腖腜腎腓腝臀腇腫臋 臨腝臩腜臩腎腗腊腧腌腙腇膭腍腨腗腂腧腡腓臋腘腣腒腝膿膠膻腜膐膅腰腺膕膈膔腼腬腶腀膎膳腇臭腊膪腩腕腗腂腧腌腙腇腩腆 腌腝膳腆膁腛至膡腐腧腌腙 腞臚腝腃腄腘腣臦腙腛腕腗腂腧臂腘腞 膐膅腰腺膕膈膔腼腬腶腀膎膳腝膬臼膈膔腼腬 腶腀膎膥臋腝膻臫腜膞腄臝腥腝臷腺腮腻腘腁腧 腇腫腜膪腎腓臗臄腜腖腂腗膡臶腐腧腍腊腆腈腏腋腎腉腅腇腀腌腑腙 膐膅腰腺膕膈膔腼腬腶腀膎膳臟腜 4 腖腝 腐腛腩腔膐膅腰腺膕膨臱膝臃E1膐膅 腰腺膕膶臅臃E2膐膅腰腺膕膑腯腀腵 E3腅腤腟 26S 膈膔腼腬腶腀膎腜腤腕腗臁臲腍腨腗腅 腌腨腥腝臍腜腤腕腗腨腖腸膕膄腱臜 膬臜膑腳膕臐膬腜膐膅腰腺膕腪腮腶膉膈腺腾膶臅腍腑 2,31膐膅腰腺膕腞 1978 Ciechanover Hershko 腜腤腕腗 膹腍腨腓 76 腬膍膂臏8kDa 自腜臧腍腛腸膕膄腱臜腘腁腧 4腨腖腸膕膄腱臜腜膶臅腎腓膐膅腰腺膕腝膑腳膕臐 膬腜腍腥腜臙腝膐膅腰腺膕腇膶臅腎腌腝膲腦腜腤腦腘腈腓膋膑膐膅腰腺膕膝腸膕膄腱臜腞腀腂26S 膈膔腼腬腶腀膎腜腤腕腗 臛腍腨 膡腍腨 5῍ῑ7臒腤腦腛腧 E1 腅腤腟 E2 腙膗腛腦E3 臰腝臒腜腤腧腘腁腧腌腙腇腒腝腜膬臜腨腖膗臱腪膵腐腧腲膇膐膁腻腽 腇膫腡腨腗腂腧腶腜腝臁腅腤腟膩膰腝膝腜 致膌膑腬膕膀膙膟膤膟膦腜腮腤膤膟 71 71

St. Marianna University School of Medicineigakukai.marianna-u.ac.jp/idaishi/www/361/11-36... · Vol. 36, pp. 71 82, 2008 : 20 4 7 ˘ ˇˆ˙˝˛˚ ˜ 2 ! "#$%! &’( ) #* +,-./0 1

  • Upload
    others

  • View
    0

  • Download
    0

Embed Size (px)

Citation preview

Page 1: St. Marianna University School of Medicineigakukai.marianna-u.ac.jp/idaishi/www/361/11-36... · Vol. 36, pp. 71 82, 2008 : 20 4 7 ˘ ˇˆ˙˝˛˚ ˜ 2 ! "#$%! &’( ) #* +,-./0 1

� � ����������Vol. 36, pp. 71�82, 2008

����������� ������

���

���

���

���

��

���

��

��� :� 20 4 � 7 ��

�������� ����� ����� �������

��

� 2 !�"#$%!�&'(����)���#*�+,-./0� 1 ) cDNA �12��314506���7��89�:+);<,=>���?@+�/>��!A�BCDE FGH )I��! �J�?@!�&'(K�LM> �����CD0� �N#6��OP+�Q4RS O#T>I���U+ V0!"!WXCD0��+ Y!I���U'( �=. ���#ZCY![$+ \��) ]M'(!����!^_�`�a#%&4#T./\F!,bcM0� 7d'ef�D0/)'egh(i4D0 ���#Z) j,�k���lBm) V#cS���n+��,V0F!CD0 �� 1�� ���n$%!*o)p\ +,�# ���CD0 ErbB2�HER2 ����nCD0],��qLM>!) 20rCD0� ]M4-=. �������������s.!'t+u0������v�n!*o)w\ +,�#x��8CD0 RING 89�v��������v�nCD0],�c'T>!) 1999C1� j,�k!������v�n)Y!y4�qLM./0� z/�4)���n5E)0'4�\!{0!������v�n�1dV0],'( �����B|}�z/J�4&>V2~)3P4�N' �4C �� ]!s.+��,=>����#Z�K�LM./0 �� 1�� �����_�CD0�������5�Z!�:��

�� �bortezomib: Velcade PS-341� ���U���467#�&+8<>],'( �y �������������s.+��4=>9!���Z�'e!�4:�=.\0],��;LM./0��> �<!#ZCFY!�&�74�������������s.��\�cT./0],�c'E ]!s.!�=#I��J�+>?V0],)���?!G�CF�4,#T./0� @�C)�������������s.!�� �������5�Z!7�4��6�(!�A BCD0C��4�D=>��4 /.? V0�

� �������������

�������������s.) ¡4 4 !m) V#cS�����¢UBm) �E1� �����£Xm) �E2� ������v�n �E3� ¤5¥ 26S �������45T.¦�LM.¤E ]M(!§�45T.��_�¨2© ��©�!�ª�«�4�����+1�¬��a£XL­02�, 3� �� 1�� �����) 1978 4 Ciechanover, Hershko 45T.�qLM> 76 ��®l8kDa !3P4¯L#_�¨2©CD04����_�¨2©4£X=>�����!�ª�«�4L(4°!������£X= ]!±EE=45EC">²������B_�¨2©))F\26S�������45T.8³LM ?LM05��7�� GH �5E#0 E1 ¤5¥ E2 ,O#EE3 )H´! �450HX�CD0],��\Y!I4�©�����OU+µJV0¶��·���¸�M./0� z/�!¦K¤5¥¹º!LB4��������� �»��C¼�� M»�

71

71

Page 2: St. Marianna University School of Medicineigakukai.marianna-u.ac.jp/idaishi/www/361/11-36... · Vol. 36, pp. 71 82, 2008 : 20 4 7 ˘ ˇˆ˙˝˛˚ ˜ 2 ! "#$%! &’( ) #* +,-./0 1

���������� �������� ������������ !"� �����#$%&'"()*+��,-� ./01()23�,-456�7��26S 89:;<=>#?@����AB'CD�E� 20S 89:;<=>/F�GH�I�J4K

LE���MNOPQRS� 19S 89:;<=>�PA700� TUVW�� �� 1�� 19S 89:;<=># Lys-48 XPYZ[���� \�]^6� _��`��aKH4�bc6� `�#F�dd 20S89:;<=>4e1�������� _�f4�gh/gijk��� lmno>��p���7

� 1 �9q �r=s�it89:;<=>��Nu'/6.vwx

� 1 ���� �89:;<=>yz

{|}~ ����72

72

Page 3: St. Marianna University School of Medicineigakukai.marianna-u.ac.jp/idaishi/www/361/11-36... · Vol. 36, pp. 71 82, 2008 : 20 4 7 ˘ ˇˆ˙˝˛˚ ˜ 2 ! "#$%! &’( ) #* +,-./0 1

���������� ��������������������� ! 7"�������� Lys #$�%& Lys-48 '()*�+),-.�����/01�2����� 3�� ������0 �������4 5678�96�:�;�� �reviewed in Pickart et al., 2001�� <=����� >��?�@�AB �endocytosis� C>�����D0� Lys-63 '(),-.�����/ en-docytosis� DNAE�� IKK �I kappa B kinase� F��� G1H.IJ��EK���4)*L*L� �� 2��MNOP 44)*Q0GL*� 500����R;�SN��0T)*� �����.U�R 1000 VW�S)� �����EK � ��.�X�4��� ��L Y!VW0� >���:�0Z[\*L� 4;�]�P�� ^S_�0GL*96�`a; �b�'��4),c�d�e��f�0@�gh�L��

��������

�������������b�'��4),�i���jk0�lm�n!,� ��������o�I��Jpq���8�� �r���s��t�),9��uvwxy�� 1�30GL*I��Jpq�z{;�|}!9�� �~.�e���FDA� � 2003 I��Jpq'9��uvw��i4)*��),� I��Jpq � Y�C!��I��X; 20S ���������<�.��F�"���������0+eN� 401�� ��

�0�������'�oN�10�� 9��uvw0TN�I��Jpq��#�� � $�8�#�d01\*2,}n!� 4;%�n!*L�;11��L�!2�&�82� 8L� 'y} ���������i; 26S �������'�oN� 401�� >��0��n!8L-.�����'(�n�� ������.����')��+{4)*���*���8�.�������;�+N�^�0,-)*L�� ����.�8�����;�+N� 401�� DNA��E�0./8�����������;�P868�12�, 13� �� 3��;h>�8 �0¡�>�¢£�2DNA��;¤120� �>�� �-���;34n!� 4;�]n!�� ¥,� DNA ��'��N��i4�5��¦§z{;�|}!� �6¨� unpub-lished data��I��Jpq��l©ª � «¬­x4 �phaseII trial on cutaneous T-cell lymphoma by Jonsson

Comprehensive Cancer Center, NCT00182637�«¬­xV®�¯�w7 �phase II trials on advancedbronchiolo-aveolar carcinoma �BAC� or adenocar-cinoma by the Irish Clinical Oncology Research

Group NCT00513877� �G 8[!*L�� ^S�4 °� ±²;h0GL* 8}³8z{ �|}!*L8L� )³)� !}�©ª third line

V´���4)*µ[!*L� 4;96� 9;h0GL* :; 1 V�;�]n!�¶|*�·;¯L¸µ�9;h 12<0T)*�I��Jpq¹i=>�%�;���B���14�� º�<��»�

� 2 �����EK�¼?4:�

�������������b�4;h�� 73

73

Page 4: St. Marianna University School of Medicineigakukai.marianna-u.ac.jp/idaishi/www/361/11-36... · Vol. 36, pp. 71 82, 2008 : 20 4 7 ˘ ˇˆ˙˝˛˚ ˜ 2 ! "#$%! &’( ) #* +,-./0 1

a b c d

e f g h

li j k

��� HER2 ��������� ������������������������������������� !"#$�%&'()�*+�,��-./�01��2�3��� �� 1�� 45%&'()�*6���789:;<=> A�NPI-0052� �<?�@:#$�A1�BC��D�%&'()�*,EFGH�6I�15��17�� J;")KL@$ �epoxomicin� �J;MKL@$ epone-mycin�� J;"@N/$OPQ1RSTU��D� VW�����18�, 19�� J;")KL@$��XYZ[\]���%&'()�*6�� 20S%&'()�*�"^/8%@$ _`�EFGH�a�I�� b�J;")KL@$�� c:d�e �"^/8%@$ _`����a�I�20��22��J;")KL@$�fg�B���� PR-171�h�� in vitro �ij]kl]mnop��qr,

6I���stuQ123��

��������� ��������������

vwxy^$z{%��@|}y�~� ���,���� ����qr����i��� �������J:/&-$z{%�� a

�ERa� �� !"#$�%&'()�*+����i��uQ�� 01�i� �����Q�%&'()�*����p�,�3I�����Q�� 0�0� ����%&'()�*����ERa @|}y,6I�� !"#$�%&'()�*+���� ERa ��������Z 2��+�� I���8�$>���H���H���XI� �� 4��8�$>���H����� ��/@ .?¡m¢ Hsp70� Hsp90 �£fC���1 U-box !"

� 3 %&'()�*������ DNA ¤¥_`� !"#$ foci ¦g���HeLa p��c$%/'@$�BC CPT-11 ,§��� DNA2 �¨©ª_`�8$«�01 H2AX �gH2

AX� foci ¬�� �e, i�� �� foci �� u�� DNA ­®¯°�±²� !"#$¨��� foci ¬guQ� �f��� %&'()�*��� MG132 ���i !"#$p�¢�/<.%uQ�� DNA ¤¥_`� !"#$ foci �¬guQ���� ��j�� DAPI: v³´

µ¶·¸ ¹º»¼74

74

Page 5: St. Marianna University School of Medicineigakukai.marianna-u.ac.jp/idaishi/www/361/11-36... · Vol. 36, pp. 71 82, 2008 : 20 4 7 ˘ ˇˆ˙˝˛˚ ˜ 2 ! "#$%! &’( ) #* +,-./0 1

�������� CHIP � �� ������������������ ERa ����� ��� !"� "�#$�%&�' ERa %(�����%��24�, 25�� ����)*+� !'� ,-.��/012������34��5#�� �% !' ERa%67893:;��� <%=>?��@ABCD�E�F��� MG132�G�H�/I�� ERa'JKL" ERa346789'�F"�?MH�/26�� ERaNO9@AP�Q� �ER responsive element; ERE� %67893' ERE R3 ERa%ST��UVWX�Y��?:���27�, 28� �� 4�� �%Z� ERE R% ERa %[\3012���@ABCD�E&�]���� @ABCD�E�^_"?ERa�`Ca�b�Q��012������cTd ERE R3e���f�� 2g�hi% ERa

%@AP�Q�j%ST^_H�� ��3k#���lm('� 1� 012�������� E6AP29�, 30�� MDM231�� EFP32�� 2� 20S @ABCD�E%no0pqr LMP233� ? 19S @ABCD�E%no0pqr Rpt6�TRIP1�SUG127�� 3�LMP2? ERa �st"�BAu�vw@Q�`Ca�b�Q� SRC32�� E6AP ? ERa �st"�BAu�vw@Q�`Ca�b�Q� AIB134�

�� AIB1 'xyI�3z{|��}W� f/� AIB1�z{|H~/���'� ����xy}4����������xy���H�� �����%�-%�%� ERa% !3���}4�"35�� }�����?3 ERa C�Q�p�r% �b�r��r �ful-vestrant, ICI182780� ? RU58668 ' ERa % !���"36�� �b�r��r' ERa �R��/ERE R%nua�����H~� �%012������34 !���H~� �� AIB1 'C�Q�p�r�'�-C�p�r��'��rA��)*+3 ERa% !���" �� 4�� �/�� AIB1 %�F'��rA��34��  H� ERa% !��F�� ERa3467��F"� fulvestrant¡ GW5638 �  H� ERa

% !'^_���34�� ���%S¢��� �b�r��r? AIB1 ^_�%£�34 ER�9xy%¤�3}¥¦§¨¢©ªH�� R«��'012���@ABCD�E&�3����¬�%?��­®u�H������ 012���@ABCD�E&��¯°"��?��±²���� �%³´��µ?� 012���@ABCD�E&�34 ERa !&� �� 4�'¶�P�)*9y%¤�%·+?�¸²9�¹��

� 4 012���@ABCD�E&�?��rA��º»¼�

012���@ABCD�E&�?y¤� 75

75

Page 6: St. Marianna University School of Medicineigakukai.marianna-u.ac.jp/idaishi/www/361/11-36... · Vol. 36, pp. 71 82, 2008 : 20 4 7 ˘ ˇˆ˙˝˛˚ ˜ 2 ! "#$%! &’( ) #* +,-./0 1

���

HER2, EGFR ����������� ��

��������� ������������������� ���� �Growth Fac-tor, GF� ����������� �� ������ �GFR� ��� EGFR �epidermalgrowth factor receptor, �� ErbB1�HER1� HER2 �ErbB2�Neu� � �!�"���"#$��%��&�'�(��� ����)�*����37��39�� GFR �+,%#��$-./�01�����23 ERa ���45�67� � �7� ��2����EGFR 45�6��� EGF 7� � 2 ��8�� 9� 2��8��:����6';��#$��%��&�<�8=>� ?��@ABC����� Grb2 D Shc �4�E8=F� <�8G��� 5A�� 9�H� EGFR ��I�#$��JK�LM4�E8 +,%#�45�&��� Cbl34�E8�40�� Cbl � EGFR N�OP Cbl �<�8QRST9G� U�OV EGFR Cbl ��:��W+,%#�8=F� @�6/�0�XYF� 99�/�-Z��=F��23�[ \��=F�� 9�] ^5-Z_AZ�6(`Cab�cdQ��:���3� efgF���� c�4�E8=F� HER2 Cbl �OP��[ Cbl 7� �2������41�� HER2 �h �*G� HER2�EGFR �i-$ 2 ���!j� EGFR �Cbl 7� ��2Q"#�� U�<�Q�)=>�41��44� �� 5B�� k3�l�9 �mnopqr_��� HER2 � Tyr1112 �4�E8 Cbl �OPQRST9�� HER2 Q�2�$%G� �� 5B��c�� 45�6�7� � HER2 ��2 �

ERa ��� Hsp70� Hsp90 OP�� CHIP ��:�stF�45��48�� ���:�� 9�a&Q'(G�)u � mnpor_ �*��v��w��xVQy+G�9 ��S�� w��u�,-�z.��{ Hsp90 �OPG�|�}�r;���geldanamycin� � ~ ��z.���� ���CHIP 7� � HER2 ��2 #$��"#)��� CI-1033 ��:�'(=F��� CI-1033 |�}�r;�� /0���Q1� �"#G�49��

BRCA1� basal-like ���

.$r��&2�uQ34 ����567��� mnopqr_ �trastuzumab� �%8�����6 �� 10 9�:;Q �� �������<���� HER2 <������=> �?��� U�OV �� ER ��� PR ���HER2 ���� (s�@[A����� �t��m4�^5-Z_����C$�q.`=F���� m4�^5-Z_��� cDNA r;C$.�;�B����C��*$A�;4����{�D=F� 5���_�;� G�t� lumi-nal A� luminal B� normal breast-like� HER2 h �*� basal-like ��� basal-like ������cEG�9 �t�:�� 9�"��� � basal��FG���r�������;m�n#� 5�6�14� 17� ,'�#�Q�*����50��52��� ERa�PR� HER2 Q�*������ �������H15������ 9��_�; A����������{�I�QJ��9 �g� U�A���K � ���L��A���K�MS[��G��F��NOQ����� basal-like �����C��*$A�;�� BRCA1 :���� P���� ¡¢G�9 �g� BRCA1 �C�:�£¤� BRCA11��a&QL���� basal-like ���QS�G¥� ��efgF���� ¦H��R����� FG��N� � BRCA1 k�§p53�:�Q%8��r¨o �S�©>� basal-like ���Q!j�� BRCA1 DNA TUªVWXY�Z[��{� BRCA1 �o��6��S��� DNA \]�^G�«_��`a�b(G�����:� BRCA1 basal-like����k¬�w��u«_�Q2BG�F�St��������BRCA1 � ��cy�k¬�#B`C­;�mab� DNA XYab� 34�#®ab�¯�k�� p53 3�°_deI �fgChab�±²i�³jG�deI� ��k����� DNA TUªVWXY�k¬� BRCA1 �l´ 1�mµfXYQnok9�� BRCA2 D Rad51 �¯�@ABC��Q\]I³�$%G�'¶Z@������� ·[��� 9�1��'�¸q0 pq �2a=F�� G�t�� rstDm¹;/'n�&2�u�¯���DNATUªVW�!j� � �º ATM ��:�\]I³�»om� H2AX �4

u?v¼ wxyz76

76

Page 7: St. Marianna University School of Medicineigakukai.marianna-u.ac.jp/idaishi/www/361/11-36... · Vol. 36, pp. 71 82, 2008 : 20 4 7 ˘ ˇˆ˙˝˛˚ ˜ 2 ! "#$%! &’( ) #* +,-./0 1

� 5 ����������� �� EGFR�HER2����

����������� ������ 77

77

Page 8: St. Marianna University School of Medicineigakukai.marianna-u.ac.jp/idaishi/www/361/11-36... · Vol. 36, pp. 71 82, 2008 : 20 4 7 ˘ ˇˆ˙˝˛˚ ˜ 2 ! "#$%! &’( ) #* +,-./0 1

����� �� 3e�� ����� �� ������������ RNF8 �������� !"�� Lys-63 #$%�&������'�()*�53��55� �� 3f��� ��&������'� RAP80 +,-./ BRCA1 ��0*��56��58�� BRCA1 1BARD1 ��2� RING2 �3%����������+()���59��62�� ��4��56� BRCA1- BARD1 �7819�*�/: :� ;<=1�BRCA1- BARD1 �78�>?�./ NPM1 +@A./5�63�� ��4��5:/2 NPM1 ���������B/CDE����FG��H�IJ� BRCA2 � Rad51 ���K@LMN�O./P�./:�2��QN/:��R�STU�V�WDXYZ�[\]^1��DNA _�'`abc�56� !"��������+�d����e=DNA_�'`a+fg��"&hZij��\]^���Y�"jkhC��l�^mn�W"Xo�� DNA CD!��n����o!Wj��mnpqWj���Krst+2uvwx���� �y� BRCA1 4��zw��d*�/:� basal-like {�|�1}�L~��T/DNAbc���\]*����e=� ��|^�./st�����������

����

��� ���5���(�|�56�WDXYZ�[\]��������+���������� ���y�������*��vwx���� WDXYZ�[1�|���ee�=��/������/��  zw�¡�B/:��2ee�=�� ¢�\]^�£�¤¥�¦§���¨x©ª�����vw��BU��1«¬�T������ ��� ��«­  I®¯ §�+ �����������+° ��������� *=�¦§��± :��|^�²¨2��*������������WDXYZ�[4�+° �.U³��´�.U:�

���

1� Ohta. T., Michel. J. J , Schottelius, A. J, andXiong, Y.: ROC1, a homolog of APC11, repre-

sents a family of cullin partners with an associ-

ated ubiquitin ligase activity. Mol. Cell 1999;

3: 535�541.

2� Hershko A and Ciechanover A. The ubiquitinsystem. Annu Rev Biochem 1998; 67: 425-

479.

3� Pickart CM and Eddins MJ. Ubiquitin: struc-tures, functions, mechanisms. Biochim Bio-

phys Acta 2004; 1695: 55-72.

4� Ciehanover A, Hod Y and Hershko A: A heat-stable polypeptide component of an ATP-

dependent proteolytic system from reticulo-

cytes. Biochem. Biophys. Res. Commun 1978;

81: 1100�1105.5� Pickart CM. Back to the future with ubiquitin.Cell 2004; 116: 190.

6� Mukhopadhyay D and Riezman H. Protea-some-independent functions of ubiquitin in en-

docytosis and signaling. Science 2007; 315:

201�205.7� Ohta T and Fukuda M. Ubiquitin and breastcancer. Oncogene 2004; 23: 2079�2088.

8� Hideshima T, Richardson P, Chauhan D,Palombella VJ, Elliott PJ, Adams J and Ander-

son KC. The proteasome inhibitor PS-341

inhibits growth, induces apoptosis, and over-

comes drug resistance in human multiple mye-

loma cells. Cancer Res 2001; 61: 3071�3076.9� Richardson PG, Barlogie B, Berenson J, Sing-hal S, Jagannath S, Irwin D, Rajkumar SV,

Srkalovic G, Alsina M, Alexanian R, Siegel D,

Orlowski RZ, Kuter D, Limentani SA, Lee S,

Hideshima T, Esseltine DL, Kau#man M, Ad-

ams J, Schenkein DP and Anderson KC. A

phase 2 study of bortezomib in relapsed, refrac-

tory myeloma. N Engl J Med 2003; 348:

2609�2617.10� Adams J. The proteasome: structure, function,

and role in the cell. Cancer Treat Rev 2003; 29

Suppll 1: 3-9.

11� Hideshima T, Chauhan D, Richardson P, Mit-siades C, Mitsiades N, Hayashi T, Munshi N,

Dang L, Castro A, Palombella V, Adams J and

Anderson KC. NF-kappa B as a therapeutic

target in multiple myeloma. J Biol Chem 2002;

277: 16639�16647.12� Dantuma NP, Groothuis TA, Salomons FA

µ¶·¸ ¹º»¼78

78

Page 9: St. Marianna University School of Medicineigakukai.marianna-u.ac.jp/idaishi/www/361/11-36... · Vol. 36, pp. 71 82, 2008 : 20 4 7 ˘ ˇˆ˙˝˛˚ ˜ 2 ! "#$%! &’( ) #* +,-./0 1

and Neefjes J. A dynamic ubiquitin equilib-

rium couples proteasomal activity to chroma-

tin remodeling. J Cell Biol 2006; 173: 19-26.

13� Mailand N, Bekker-Jensen S, Faustrup H, Me-lander F, Bartek J, Lukas C and Lukas J.

RNF8 ubiquitylates histones at DNA double-

strand breaks and promotes assembly of repair

proteins. Cell 2007; 131: 887-900.

14� Yang CH, Gonzalez-Angulo AM, Reuben JM,Booser DJ, Pusztai L, Krishnamurthy S, Es-

seltine D, Stec J, Broglio KR, Islam R, Horto-

bagyi GN and Cristofanilli M. Bortezomib

�VELCADE� in metastatic breast cancer: phar-macodynamics, biological e#ects, and predic-

tion of clinical benefits. Ann Oncol 2006; 17:

813�817.15� Feling RH, Buchanan GO, Mincer TJ,

Kau#man CA, Jensen PR and Fenical W. Sa-

linosporamide A: a highly cytotoxic protea-

some inhibitor from a novel microbial source,

a marine bacterium of the new genus salino-

spora. Angew Chem Int Ed Engl 2003; 42:

355-357.

16� Chauhan D, Catley L, Li G, Podar K, Hide-shima T, Velankar M, Mitsiades C, Mitsiades

N, Yasui H, Letai A, Ovaa H, Berkers C,

Nicholson B, Chao TH, Neuteboom ST, Rich-

ardson P, Palladino MA, Anderson KC. A

novel orally active proteasome inhibitor in-

duces apoptosis in multiple myeloma cells with

mechanisms distinct from Bortezomib. Cancer

Cell 2005; 8: 407-419.

17� Joazeiro CA, Anderson KC and Hunter T.Proteasome inhibitor drugs on the rise. Cancer

Res 2006; 66: 7840-7842.

18� Hanada M, Sugawara K, Kaneta K, Toda S,Nishiyama Y, Tomita K, Yamamoto H, Kon-

ishi M and Oki T. Epoxomicin, a new antitu-

mor agent of microbial origin. J Antibiot �To-kyo� 1992; 45: 1746-1752.

19� Sugawara K, Hatori M, Nishiyama Y, TomitaK, Kamei H, Konishi M and Oki T. Epone-

mycin, a new antibiotic active against B 16

melanoma. I. Production, isolation, structure

and biological activity. J Antibiot �Tokyo�1990; 43: 8-18.

20� Sin N, KimKB, Elofsson M, Meng L, Auth H,Kwok BH and Crews CM. Total synthesis of

the potent proteasome inhibitor epoxomicin: a

useful tool for understanding proteasome biol-

ogy. Bioorg Med Chem Lett 1999; 9: 2283-

2288.

21� Meng L, Kwok BH, Sin N and Crews CM.Eponemycin exerts its antitumor e#ect through

the inhibition of proteasome function. Cancer

Res 1999; 59: 2798-2801.

22� Meng L, Mohan R, Kwok BH, Elofsson M,Sin N and Crews CM. Epoxomicin, a potent

and selective proteasome inhibitor, exhibits in

vivo antiinflammatory activity. Proc Natl

Acad Sci USA 1999; 96: 10403�10408.23� Stapnes C, Doskeland AP, Hatfield K, ErsvaerE, Ryningen A, Lorens JB, Gjertsen BT, Brus-

erud O and Br J Haematol. The proteasome

inhibitors bortezomib and PR-171 have anti-

proliferative and proapoptotic e#ects on pri-

mary human acute myeloid leukaemia cells

2007; 136: 814�828.24� Tateishi Y, Kawabe Y, Chiba T, Murata S,Ichikawa K, Murayama A, Tanaka K, Baba T,

Kato S and Yanagisawa J. Ligand-dependent

switching of ubiquitin-proteasome pathways

for estrogen receptor. EMBO J 2004; 23:

4813�4823.25� Fan M, Park A and Nephew KP. CHIP �car-boxyl terminus of Hsc70-interacting protein�promotes basal and geldanamycin-induced

degradation of estrogen receptor-alpha. Mol

Endocrinol 2005; 19: 2901�2914.26� Lonard DM, Nawaz Z, Smith CL and O[Mal-

ley BW. The 26S proteasome is required for

estrogen receptor-alpha and coactivator turn-

over and for e$cient estrogen receptor-alpha

transactivation. Mol Cell 2000; 5: 939�948.27� Reid G, Hubner MR, Metivier R, Brand H,

Denger S, Manu D, Beaudouin J, Ellenberg J

and Gannon F. Cyclic, proteasome-mediated

turnover of unliganded and liganded ERalpha

����������� ������ 79

79

Page 10: St. Marianna University School of Medicineigakukai.marianna-u.ac.jp/idaishi/www/361/11-36... · Vol. 36, pp. 71 82, 2008 : 20 4 7 ˘ ˇˆ˙˝˛˚ ˜ 2 ! "#$%! &’( ) #* +,-./0 1

on responsive promoters is an integral feature

of estrogen signaling. Mol Cell 2003; 11: 695-

707.

28� Zhang H, Sun L, Liang J, Yu W, Zhang Y,Wang Y, Chen Y, Li R, Sun X, Shang Y. The

catalytic subunit of the proteasome is engaged

in the entire process of estrogen receptor-

regulated transcription. EMBO J 2006; 25:

4223�4233.29� Nawaz Z, Lonard DM, Smith CL, Lev-Lehman E, Tsai SY, Tsai MJ and O[Malley

BW. The Angelman syndrome-associated pro-

tein, E6-AP, is a coactivator for the nuclear

hormone receptor superfamily. Mol Cell Biol

1999; 19: 1182�1189.30� Li L, Li Z, Howley PM and Sacks DB. E6AP

and calmodulin reciprocally regulate estrogen

receptor stability. J Biol Chem 2006; 281:

1978�1985.31� Saji S, Okumura N, Eguchi H, Nakashima S,Suzuki A, Toi M, Nozawa Y, Saji S and Hay-

ashi S. MDM2 enhances the function of estro-

gen receptor alpha in human breast cancer

cells. Biochem Biophys Res Commun 2001;

281: 259�265.32� Nakajima A, Maruyama S, Bohgaki M, Miya-jima N, Tsukiyama T, Sakuragi N and Hatak-

eyama S. Ligand-dependent transcription of

estrogen receptor alpha is mediated by the

ubiquitin ligase EFP. Biochem Biophys Res

Commun 2007; 357: 245�251.33� Zhang H, Sun L, Liang J, Yu W, Zhang Y,

Wang Y, Chen Y, Li R, Sun X and Shang Y.

The catalytic subunit of the proteasome is en-

gaged in the entire process of estrogen receptor-

regulated transcription. EMBO J 2006; 25:

4223�4233.34� Shao W, Keeton EK, McDonnell DP andBrown M. Coactivator AIB1 links estrogen

receptor transcriptional activity and stability.

Proc Natl Acad Sci USA 2004; 101:

11599�11604.35� Wijayaratne AL and McDonnell DP. The hu-

man estrogen receptor-alpha is a ubiquitinated

protein whose stability is a#ected di#erentially

by agonists, antagonists, and selective estrogen

receptor modulators. J Biol Chem 2001; 276:

35684�35692.36� Marsaud V, Gougelet A, Maillard S and Re-noir JM. Various phosphorylation pathways,

depending on agonist and antagonist binding

to endogenous estrogen receptor alpha �ERal-pha�, di#erentially a#ect ERalpha extractabil-ity, proteasome-mediated stability, and tran-

scriptional activity in human breast cancer

cells. Mol Endocrinol 2003; 17: 2013�2027.37� Harari D and Yarden Y: Molecular mecha-nisms underlying ErbB2�HER2 action in breastcancer. Oncogene 2000; 19: 6102-6114.

38� Bhargava R, GeraldWL, Li AR, Pan Q, Lal P,Ladanyi M and Chen B. EGFR gene amplific-

ation in breast cancer: correlation with epider-

mal growth factor receptor mRNA and protein

expression and HER-2 status and absence of

EGFR-activating mutations. Mod Pathol

2005; 18: 1027�1033.39� Park K, Han S, Shin E, Kim HJ and Kim JY.

EGFR gene and protein expression in breast

cancers. Eur J Surg Oncol 2007; 33: 956�960.40� Olayioye MA, Neve RM, Lane HA Hynes NE.The ErbB signaling network: receptor hetero-

dimerization in development and cancer.

EMBO J 2000; 19: 3159�3167.41� Muthuswamy SK, Gilman M and Brugge JS:Controlled dimerization of ErbB receptors pro-

vides evidence for di#erential signaling by ho-

mo- and heterodimers. Mol Cell Biol 1999; 19:

6845-6857.

42� Graus-Porta D, Beerli RR, Daly JM and Hy-nes NE. ErbB-2, the preferred heterodimeriza-

tion partner of all ErbB receptors, is a mediator

of lateral signaling. EMBO J 1997; 16:

1647�1655.43� Levkowitz G, Waterman H, Zamir E, Kam Z,Oved S, Langdon WY, Beguinot L, Geiger B

and Yarden Y. c-Cbl�Sli-1 regulates endocyticsorting and ubiquitination of the epidermal

growth factor receptor. Genes Dev 1998; 12:

���� ����80

80

Page 11: St. Marianna University School of Medicineigakukai.marianna-u.ac.jp/idaishi/www/361/11-36... · Vol. 36, pp. 71 82, 2008 : 20 4 7 ˘ ˇˆ˙˝˛˚ ˜ 2 ! "#$%! &’( ) #* +,-./0 1

3663�3674.44� Lenferink AE, Pinkas-Kramarski R, van de

Poll ML, van Vugt MJ, Klapper LN, Tzahar

E, Waterman H, Sela M, van Zoelen EJ and

Yarden Y. Di#erential endocytic routing of

homo- and hetero-dimeric ErbB tyrosine ki-

nases confers signaling superiority to receptor

heterodimers. EMBO J 1998; 17: 3385�3397.45� Zhou P, Fernandes N, Dodge IL, Reddi AL,Rao N, Safran H, DiPetrillo TA, Wazer DE,

Band V and Band H. ErbB2 degradation me-

diated by the co-chaperone protein CHIP. J

Biol Chem 2003; 278: 13829�13837.46� Xu W, Marcu M, Yuan X, Mimnaugh E, Pat-terson C, Neckers L. Chaperone-dependent E3

ubiquitin ligase CHIP mediates a degradative

pathway for c-ErbB2�Neu. Proc Natl Acad SciUSA 2002; 99: 12847�12852.

47� Citri A, Alroy I, Lavi S, Rubin C, Xu W,Grammatikakis N, Patterson C, Neckers L,

Fry DW and Yarden Y. Drug-induced ubiqui-

tylation and degradation of ErbB receptor ty-

rosine kinases: implications for cancer therapy.

EMBO J 2002; 21: 2407�2417.48� Connell P, Ballinger CA, Jiang J, Wu Y,Thompson LJ, Hohfeld J and Patterson C.

The co-chaperone CHIP regulates protein tri-

age decisions mediated by heat-shock proteins.

Nat Cell Biol 2001; 3: 93-96.

49� Honrado E, Osorio A, Palacios J and BenitezJ. Pathology and gene expression of hereditary

breast tumors associated with BRCA1, BRCA2

and CHEK2 gene mutations. Oncogene 2006;

25: 5837�5845.50� Perou CM, Sorlie T, Eisen MB, van de Rijn M,Je#rey SS, Rees CA, Pollack JR, Ross DT,

Johnsen H, Akslen LA et al: Molecular por-

traits of human breast tumours. Nature 2000;

406: 747�752.51� Nielsen TO, Hsu FD, Jensen K, Cheang M,

Karaca G, Hu Z, Hernandez-Boussard T, Li-

vasy C, Cowan D, Dressler L et al: Immuno-

histochemical and clinical characterization of

the basal-like subtype of invasive breast carci-

noma. Clin Cancer Res 2004; 10: 5367�5374.52� Sorlie T, Tibshirani R, Parker J, Hastie T,Marron JS, Nobel A, Deng S, Johnsen H,

Pesich R, Geisler S et al: Repeated observation

of breast tumor subtypes in independent gene

expression data sets. Proc Natl Acad Sci USA

2003; 100: 8418�8423.53� Kolas NK, Chapman JR, Nakada S, Ylanko J,Chahwan R, Sweeney FD, Panier S, Mendez

M, Wildenhain J, Thomson TM, Pelletier L,

Jackson SP and Durocher D. Orchestration of

the DNA-damage response by the RNF8 ubiq-

uitin ligase. Science 2007; 318: 1637�1640.54� Huen MS, Grant R, Manke I, Minn K, Yu X,Ya#e MB and Chen J. RNF8 transduces the

DNA-damage signal via histone ubiquitylation

and checkpoint protein assembly. Cell 2007;

131: 901�914.55� Mailand N, Bekker-Jensen S, Faustrup H, Me-lander F, Bartek J, Lukas C and Lukas J.

RNF8 ubiquitylates histones at DNA double-

strand breaks and promotes assembly of repair

proteins. Cell 2007; 131: 887�900.56� Kim H, Chen J, Yu X. Ubiquitin-binding pro-tein RAP80 mediates BRCA1-dependent DNA

damage response. Science 2007; 316: 1202�1205.

57� Sobhian B, Shao G, Lilli DR, Culhane AC,Moreau LA, Xia B, Livingston DM and

Greenberg RA. RAP80 targets BRCA1 to spe-

cific ubiquitin structures at DNA damage sites.

Science 2007; 316: 1198�1202.58� Wang B, Matsuoka S, Ballif BA, Zhang D,Smogorzewska A, Gygi SP and Elledge SJ.

Abraxas and RAP80 form a BRCA1 protein

complex required for the DNA damage re-

sponse. Science 2007; 316: 1194�1198.59� Hashizume R, Fukuda M, Maeda I, Nishi-kawa H, Oyake D, Yabuki Y, Ogata H and

Ohta T. The RING heterodimer BRCA1-

BARD1 is a ubiquitin ligase inactivated by a

breast cancer-derived mutation. J Biol Chem

2001; 276: 14537�14540.60� Nishikawa H, Ooka S, Sato K, Arima K, Oka-

����������� ������ 81

81

Page 12: St. Marianna University School of Medicineigakukai.marianna-u.ac.jp/idaishi/www/361/11-36... · Vol. 36, pp. 71 82, 2008 : 20 4 7 ˘ ˇˆ˙˝˛˚ ˜ 2 ! "#$%! &’( ) #* +,-./0 1

moto J, Klevit RE, Fukuda M and Ohta T.

Mass spectrometric and mutational analyses

reveal Lys-6-linked polyubiquitin chains cata-

lyzed by BRCA1-BARD1 ubiquitin ligase. J

Biol Chem 2004; 279: 3916�3924.61� Brzovic PS, Kee#e JR, Nishikawa H, Miya-

moto K, Fox D, 3rd, Fukuda M, Ohta T and

Klevit R. Binding and recognition in the as-

sembly of an active BRCA1�BARD1 ubiquitin-ligase complex. Proc Natl Acad Sci USA 2003;

100: 5646-5651.

62� Wu-Baer F, Lagrazon K, Yuan W and Baer R.

The BRCA1 �BARD1 heterodimer assemblespolyubiquitin chains through an unconven-

tional linkage involving lysine residue K6 of

ubiquitin. J Biol Chem 2003; 278: 34743�34746.

63� Sato K, Hayami R, Wu W, Nishikawa T,Nishikawa H, Okuda Y, Ogata H, Fukuda M

and Ohta T. Nucleophosmin�B23 is a candi-date substrate for the BRCA1-BARD1 ubiq-

uitin ligase. J Biol Chem 2004; 279: 30919�30922.

���� ����82

82