Proteasomal and Genetic Inactivation of the NF1 Tumor Suppressor in Gliomagenesis

被引：108

作者：

McGillicuddy, Lauren T. ^{[1
,2
,3
]}

Fromm, Jody A. ^{[1
,2
,3
]}

Hollstein, Pablo E. ^{[1
,2
,3
]}

Kubek, Sara ^{[4
]}

Beroukhim, Rameen ^{[2
,3
,5
,6
]}

De Raedt, Thomas ^{[1
,2
,3
,7
]}

Johnson, Bryan W. ^{[1
,2
,3
,7
]}

Williams, Sybil M. G. ^{[1
,2
,3
]}

Nghiemphu, Phioanh ^{[8
]}

Liau, Linda M. ^{[9
]}

Cloughesy, Tim F. ^{[8
]}

Mischel, Paul S. ^{[10
]}

Parret, Annabel ^{[11
,12
]}

Seiler, Jeanette ^{[11
,12
]}

Moldenhauer, Gerd ^{[13
]}

Scheffzek, Klaus ^{[11
,12
]}

Stemmer-Rachamimov, Anat O. ^{[3
,14
]}

Sawyers, Charles L. ^{[15
]}

Brennan, Cameron ^{[16
,17
]}

Messiaen, Ludwine ^{[18
]}

Mellinghoff, Ingo K. ^{[4
,15
,19
]}

Cichowski, Karen ^{[1
,2
,3
,7
]}

机构：

[1] Brigham & Womens Hosp, Div Genet, Boston, MA 02115 USA

[2] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Boston, MA 02115 USA

[4] Cornell Univ, Weill Cornell Med Coll, Dept Pharmacol, New York, NY 10021 USA

[5] Broad Inst Massachusetts Inst Technol & Harvard U, Cambridge, MA 02142 USA

[6] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[7] Dana Farber Harvard Canc Ctr, Ludwig Ctr, Boston, MA 02115 USA

[8] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA

[9] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurosurg, Los Angeles, CA 90095 USA

[10] Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA

[11] European Mol Biol Lab, Struct & Computat Biol Unit, D-69117 Heidelberg, Germany

[12] European Mol Biol Lab, Dev Biol Unit, D-69117 Heidelberg, Germany

[13] German Canc Res Ctr, Translat Immunol Unit, D-69120 Heidelberg, Germany

[14] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

[15] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[16] Cornell Univ, Weill Cornell Med Coll, Dept Neurosurg, New York, NY 10021 USA

[17] Mem Sloan Kettering Canc Ctr, Dept Neurosurg, New York, NY 10065 USA

[18] Univ Alabama, Dept Genet, Med Genom Lab, Birmingham, AL 35242 USA

[19] Mem Sloan Kettering Canc Ctr, Dept Neurol, New York, NY 10065 USA

来源：

CANCER CELL | 2009年 / 16卷 / 01期

关键词：

NEUROFIBROMATOSIS TYPE-1 GENE; PROTEIN-KINASE-C; HUMAN GLIOBLASTOMA-MULTIFORME; SOMATIC MUTATIONS; UBIQUITIN LIGASE; BRAIN-TUMORS; CELLS; SENESCENCE; ACTIVATION; PATHWAY;

D O I：

10.1016/j.ccr.2009.05.009

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Loss-of-function mutations in the NF1 tumor suppressor result in deregulated Ras signaling and drive tumorigenesis in the familial cancer syndrome neurofibromatosis type I. However, the extent to which NF1 inactivation promotes sporadic tumorigenesis is unknown. Here we report that NF1 is inactivated in sporadic gliomas via two mechanisms: excessive proteasomal degradation and genetic loss. NF1 protein destabilization is triggered by the hyperactivation of protein kinase C (PKC) and confers sensitivity to PKC inhibitors. However, complete genetic loss, which only occurs when p53 is inactivated, mediates sensitivity to mTOR inhibitors. These studies reveal an expanding role for NF1 inactivation in sporadic gliomagenesis and illustrate how different mechanisms of inactivation are utilized in genetically distinct tumors, which consequently impacts therapeutic sensitivity.

引用

页码：44 / 54

页数：11