Chemico-genetic strategies to inhibit the leukemic potential of threonine aspartase-1
Chemico-genetic strategies to inhibit the leukemic potential of threonine aspartase-1
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抑制苏氨酸天冬氨酸酶-1 的白血病潜力的化学遗传学策略
DOI：
10.1038/bcj.2012.22
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发表时间：
2012
影响因子：
12.8
通讯作者：
Stauber
中科院分区：
文献类型：
--
作者：
Wünsch;Heider;Tenzer;Knauer;Stauber
混合系白血病(MLL)基因与多个配对基因的染色体重排常见于急性髓系白血病和急性淋巴细胞性白血病。1，2尽管t(4；11)介导的白血病的发病机制仍在讨论中，但AF4MLL融合基因的表达可增强CD34-TUE细胞的再繁殖能力，并导致以疑似急性淋巴细胞白血病为主的小鼠模型的发生。1，2 AF4MLL蛋白含有苏氨酸天冬氨酸酶-1(Taspase1)的切割位点。1-4经Taspase1处理后，AF4 MLL裂解产物形成抵抗Siah介导的降解的蛋白质复合体并激活致癌程序。此外，Taspase1在液体和固体人类癌症中过表达，这表明Taspase1被用于促进和维持肿瘤的发生。6由于Taspase1在小鼠体内的基因缺失不会产生明显的缺陷，3Taspase1的抑制可能提供新的抗癌策略，包括治疗白血病。人Taspase1通过识别保守的多肽基序(Q3[F，I，L，V]2D1kG10 x20 D30 D40)，编码一个由420个氨基酸组成的反式切割底物的蛋白酶。4不幸的是，Taspase1的S活性不受常见的蛋白酶抑制剂的影响，因此目前排除了对其临床和治疗的评估
Chromosomal rearrangements of the mixed lineage leukemia (MLL) gene with numerous partner genes are frequently found in acute myeloid and acute lymphoblastic leukemia. 1, 2 Although the pathomechanism of t (4; 11)-mediated leukemia is still being discussed, expression of the AF4 MLL fusion was found to enhance the repopulating potential of CD34þ cells and lead to the development of predominantly proB-acute lymphoblastic leukemia in a mouse model. 1, 2 The AF4 MLL protein contains cleavage sites for threonine aspartase-1 (Taspase1). 1–4 Upon processing by Taspase1, the AF4 MLL cleavage products form a protein complex resistant to SIAH-mediated degradation and activate oncogenic programs. 3, 5 Furthermore, Taspase1 is overexpressed in liquid and solid human cancers, suggesting thatTaspase1 is co-opted to promote and sustain tumorigenesis. 6 As genetic deletion of Taspase1 in the mouse produced no overt deficiencies, 3 inhibition of Taspase1 may offer novel anticancer strategies, including the treatment of leukemias. Human Taspase1 encodes a protease of 420 amino acids cleaving substrates in trans by recognizing a conserved peptide motif (Q3 [F, I, L, V] 2D1kG10 x20 D30 D40). 4 Unfortunately, Taspase1’s activity is not affected by common protease inhibitors, therefore currently precluding the assessment of its clinical and therapeutic
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影响因子：
11.2
作者：
Chen DY;Liu H;Takeda S;Tu HC;Sasagawa S;Van Tine BA;Lu D;Cheng EH;Hsieh JJ
通讯作者：
Hsieh JJ
影响因子：
11.2
作者：
Chen DY;Lee Y;Van Tine BA;Searleman AC;Westergard TD;Liu H;Tu HC;Takeda S;Dong Y;Piwnica-Worms DR;Oh KJ;Korsmeyer SJ;Hermone A;Gussio R;Shoemaker RH;Cheng EH;Hsieh JJ
通讯作者：
Hsieh JJ
影响因子：
4.5
作者：
Bier, Carolin;Knauer, Shirley K.;Stauber, Roland H.
通讯作者：
Stauber, Roland H.
影响因子：
20.3
作者：
Montes, Rosa;Ayllon, Veronica;Menendez, Pablo
通讯作者：
Menendez, Pablo
影响因子：
11.4
作者：
Pless, B.;Oehm, C.;Marschalek, R.
通讯作者：
Marschalek, R.