Monoallelic loss of the imprinted gene Grb10 promotes tumor formation in irradiated Nf1+/- mice.
Monoallelic loss of the imprinted gene Grb10 promotes tumor formation in irradiated Nf1+/- mice.
复制标题
DOI：
10.1371/journal.pgen.1005235
复制
发表时间：
2015-05
期刊：
影响因子：
4.5
通讯作者：
Nakamura JL
中科院分区：
文献类型：
--
作者：
Mroue R;Huang B;Braunstein S;Firestone AJ;Nakamura JL
Imprinted genes are expressed from only one parental allele and heterozygous loss involving the expressed allele is sufficient to produce complete loss of protein expression. Genetic alterations are common in tumorigenesis but the role of imprinted genes in this process is not well understood. In earlier work we mutagenized mice heterozygous for the Neurofibromatosis I tumor suppressor gene (NF1) to model radiotherapy-associated second malignant neoplasms that arise in irradiated NF1 patients. Expression analysis of tumor cell lines established from our mouse models identified Grb10 expression as widely absent. Grb10 is an imprinted gene and polymorphism analysis of cell lines and primary tumors demonstrates that the expressed allele is commonly lost in diverse Nf1 mutant tumors arising in our mouse models. We performed functional studies to test whether Grb10 restoration or loss alter fundamental features of the tumor growth. Restoring Grb10 in Nf1 mutant tumors decreases proliferation, decreases soft agar colony formation and downregulates Ras signaling. Conversely, Grb10 silencing in untransformed mouse embryo fibroblasts significantly increased cell proliferation and increased Ras-GTP levels. Expression of a constitutively activated MEK rescued tumor cells from Grb10-mediated reduction in colony formation. These studies reveal that Grb10 loss can occur during in vivo tumorigenesis, with a functional consequence in untransformed primary cells. In tumors, Grb10 loss independently promotes Ras pathway hyperactivation, which promotes hyperproliferation, an early feature of tumor development. In the context of a robust Nf1 mutant mouse model of cancer this work identifies a novel role for an imprinted gene in tumorigenesis. Cancer-causing mutations typically involve either allele inherited from parents, and the parental source of a mutant allele is not known to influence the cancer phenotype. Imprinted genes are a class of genes whose expression is determined by a specific parental allele, either maternally or paternally derived. Thus, in contrast to most genes, the pattern of inheritance (maternal or paternal-derived) strongly influences the expression of an imprinted gene. Furthermore, imprinted genes can be differentially expressed in different tissue types. This work identifies a novel link between cancer and Grb10, an imprinted gene involved in organismal metabolism and growth. In our mouse model of radiation-induced tumors, we found monoallelic Grb10 gene loss involving the parental allele responsible for protein expression. Tumors harboring genetic loss of the expressed Grb10 allele showed absent transcript and total protein levels, despite an intact remaining wildtype Grb10 allele identified by sequencing. When restored, Grb10 suppressed tumor growth by down-regulating Ras signaling. This work demonstrates a new role for an imprinted gene in tumor formation, and shows that Grb10 functions to negatively regulate Ras signaling and suppress hyperproliferation.
登录
查看更多内容
各种各样的癌症相关MTOR突变是过度激活的，可以预测雷帕霉素的敏感性。
影响因子：
28.2
作者：
Grabiner BC;Nardi V;Birsoy K;Possemato R;Shen K;Sinha S;Jordan A;Beck AH;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
30.8
作者：
Holmfeldt, Linda;Wei, Lei;Diaz-Flores, Ernesto;Walsh, Michael;Zhang, Jinghui;Ding, Li;Payne-Turner, Debbie;Churchman, Michelle;Andersson, Anna;Chen, Shann-Ching;McCastlain, Kelly;Becksfort, Jared;Ma, Jing;Wu, Gang;Patel, Samir N.;Heatley, Susan L.;Phillips, Letha A.;Song, Guangchun;Easton, John;Parker, Matthew;Chen, Xiang;Rusch, Michael;Boggs, Kristy;Vadodaria, Bhavin;Hedlund, Erin;Drenberg, Christina;Baker, Sharyn;Pei, Deqing;Cheng, Cheng;Huether, Robert;Lu, Charles;Fulton, Robert S.;Fulton, Lucinda L.;Tabib, Yashodhan;Dooling, David J.;Ochoa, Kerri;Minden, Mark;Lewis, Ian D.;To, L. Bik;Marlton, Paula;Roberts, Andrew W.;Raca, Gordana;Stock, Wendy;Neale, Geoffrey;Drexler, Hans G.;Dickins, Ross A.;Ellison, David W.;Shurtleff, Sheila A.;Pui, Ching-Hon;Ribeiro, Raul C.;Devidas, Meenakshi;Carroll, Andrew J.;Heerema, Nyla A.;Wood, Brent;Borowitz, Michael J.;Gastier-Foster, Julie M.;Raimondi, Susana C.;Mardis, Elaine R.;Wilson, Richard K.;Downing, James R.;Hunger, Stephen P.;Loh, Mignon L.;Mullighan, Charles G.
通讯作者：
Mullighan, Charles G.
影响因子：
4
作者：
Deng, Youping;Zhang, Manchao;Riedel, Heimo
通讯作者：
Riedel, Heimo
影响因子：
64.8
作者：
BOLLAG, G;MCCORMICK, F
通讯作者：
MCCORMICK, F
DOI：
10.1073/pnas.1532175100
发表时间：
2003-07-08
影响因子：
11.1
作者：
Charalambous, M;Smith, FM;Ward, A
通讯作者：
Ward, A