PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells.
PKM2 isoform-specific deletion reveals a differential requirement for pyruvate kinase in tumor cells.
复制标题
DOI：
10.1016/j.cell.2013.09.025
复制
发表时间：
2013-10-10
期刊：
影响因子：
64.5
通讯作者：
Vander Heiden MG
中科院分区：
文献类型：
--
作者：
Israelsen WJ;Dayton TL;Davidson SM;Fiske BP;Hosios AM;Bellinger G;Li J;Yu Y;Sasaki M;Horner JW;Burga LN;Xie J;Jurczak MJ;DePinho RA;Clish CB;Jacks T;Kibbey RG;Wulf GM;Di Vizio D;Mills GB;Cantley LC;Vander Heiden MG
丙酮酸激酶M2亚型（PKM2）在癌症中表达，并在调节合成代谢中发挥作用。为了确定PKM2是否是肿瘤形成或生长所必需的，我们产生了具有条件等位基因的小鼠，该条件等位基因废除PKM2表达而不破坏PKM1表达。PKM2缺失加速了aBrca1缺失驱动的乳腺癌模型中乳腺肿瘤的形成PKM2无效肿瘤显示异质性PKM1表达，PKM1在非增殖肿瘤细胞中发现，在增殖细胞中未检测到丙酮酸激酶表达。这表明PKM2不是肿瘤细胞增殖所必需的，并意味着PKM2的非活性状态与肿瘤内的增殖细胞群相关，而非增殖肿瘤细胞需要活性丙酮酸激酶。与这些发现一致，在人类肿瘤中发现了可变PKM2表达和杂合PKM2突变。这些数据表明PKM2活性的调节支持增殖和非增殖肿瘤细胞的不同代谢需求。
The pyruvate kinase M2 isoform (PKM2) is expressed in cancer and plays a role in regulating anabolic metabolism. To determine whether PKM2 is required for tumor formation or growth, we generated mice with a conditional allele that abolishes PKM2 expression without disrupting PKM1 expression. PKM2 deletion accelerated mammary tumor formation in aBrca1-loss-driven model of breast cancer. PKM2 null tumors displayed heterogeneous PKM1 expression, with PKM1 found in nonproliferating tumor cells and no detectable pyruvate kinase expression in proliferating cells. This suggests that PKM2 is not necessary for tumor cell proliferation and implies that the inactive state of PKM2 is associated with the proliferating cell population within tumors, whereas nonproliferating tumor cells require active pyruvate kinase. Consistent with these findings, variable PKM2 expression and heterozygous PKM2 mutations are found in human tumors. These data suggest that regulation of PKM2 activity supports the different metabolic requirements of proliferating and nonproliferating tumor cells.PaperClip
登录
查看更多内容
DOI：
10.1126/science.1211485
发表时间：
2011-12-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Anastasiou D;Poulogiannis G;Asara JM;Boxer MB;Jiang JK;Shen M;Bellinger G;Sasaki AT;Locasale JW;Auld DS;Thomas CJ;Vander Heiden MG;Cantley LC
通讯作者：
Cantley LC
在条件X-box结合蛋白-1（XBP1）敲除小鼠中，从肝胰岛素抵抗中从肝胰岛素抵抗中解离肌醇提取酶（IRE1α）介导的C-JUN N末端激酶激活。
DOI：
10.1074/jbc.m111.316760
发表时间：
2012-01-20
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Jurczak MJ;Lee AH;Jornayvaz FR;Lee HY;Birkenfeld AL;Guigni BA;Kahn M;Samuel VT;Glimcher LH;Shulman GI
通讯作者：
Shulman GI
丙酮酸激酶M2激活剂促进四聚体形成并抑制肿瘤发生。
影响因子：
14.8
作者：
Anastasiou, Dimitrios;Yu, Yimin;Israelsen, William J.;Jiang, Jian-Kang;Boxer, Matthew B.;Hong, Bum Soo;Tempel, Wolfram;Dimov, Svetoslav;Shen, Min;Jha, Abhishek;Yang, Hua;Mattaini, Katherine R.;Metallo, Christian M.;Fiske, Brian P.;Courtney, Kevin D.;Malstrom, Scott;Khan, Tahsin M.;Kung, Charles;Skoumbourdis, Amanda P.;Veith, Henrike;Southall, Noel;Walsh, Martin J.;Brimacombe, Kyle R.;Leister, William;Lunt, Sophia Y.;Johnson, Zachary R.;Yen, Katharine E.;Kunii, Kaiko;Davidson, Shawn M.;Christofk, Heather R.;Austin, Christopher P.;Inglese, James;Harris, Marian H.;Asara, John M.;Stephanopoulos, Gregory;Salituro, Francesco G.;Jin, Shengfang;Dang, Lenny;Auld, Douglas S.;Park, Hee-Won;Cantley, Lewis C.;Thomas, Craig J.;Heiden, Matthew G. Vander
通讯作者：
Heiden, Matthew G. Vander
SAICAR刺激丙酮酸激酶同工型M2，并在葡萄糖有限的条件下促进癌细胞的存活。
DOI：
10.1126/science.1224409
发表时间：
2012-11-23
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Keller KE;Tan IS;Lee YS
通讯作者：
Lee YS
影响因子：
16.8
作者：
Chen, Mo;David, Charles J.;Manley, James L.
通讯作者：
Manley, James L.