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  • 1
    Publication Date: 2011-03-04
    Description: The effective use of targeted therapy is highly dependent on the identification of responder patient populations. Loss of FBW7, which encodes a tumour-suppressor protein, is frequently found in various types of human cancer, including breast cancer, colon cancer and T-cell acute lymphoblastic leukaemia (T-ALL). In line with these genomic data, engineered deletion of Fbw7 in mouse T cells results in T-ALL, validating FBW7 as a T-ALL tumour suppressor. Determining the precise molecular mechanisms by which FBW7 exerts antitumour activity is an area of intensive investigation. These mechanisms are thought to relate in part to FBW7-mediated destruction of key proteins relevant to cancer, including Jun, Myc, cyclin E and notch 1 (ref. 9), all of which have oncoprotein activity and are overexpressed in various human cancers, including leukaemia. In addition to accelerating cell growth, overexpression of Jun, Myc or notch 1 can also induce programmed cell death. Thus, considerable uncertainty surrounds how FBW7-deficient cells evade cell death in the setting of upregulated Jun, Myc and/or notch 1. Here we show that the E3 ubiquitin ligase SCF(FBW7) (a SKP1-cullin-1-F-box complex that contains FBW7 as the F-box protein) governs cellular apoptosis by targeting MCL1, a pro-survival BCL2 family member, for ubiquitylation and destruction in a manner that depends on phosphorylation by glycogen synthase kinase 3. Human T-ALL cell lines showed a close relationship between FBW7 loss and MCL1 overexpression. Correspondingly, T-ALL cell lines with defective FBW7 are particularly sensitive to the multi-kinase inhibitor sorafenib but resistant to the BCL2 antagonist ABT-737. On the genetic level, FBW7 reconstitution or MCL1 depletion restores sensitivity to ABT-737, establishing MCL1 as a therapeutically relevant bypass survival mechanism that enables FBW7-deficient cells to evade apoptosis. Therefore, our work provides insight into the molecular mechanism of direct tumour suppression by FBW7 and has implications for the targeted treatment of patients with FBW7-deficient T-ALL.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3076007/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3076007/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Inuzuka, Hiroyuki -- Shaik, Shavali -- Onoyama, Ichiro -- Gao, Daming -- Tseng, Alan -- Maser, Richard S -- Zhai, Bo -- Wan, Lixin -- Gutierrez, Alejandro -- Lau, Alan W -- Xiao, Yonghong -- Christie, Amanda L -- Aster, Jon -- Settleman, Jeffrey -- Gygi, Steven P -- Kung, Andrew L -- Look, Thomas -- Nakayama, Keiichi I -- DePinho, Ronald A -- Wei, Wenyi -- GM089763/GM/NIGMS NIH HHS/ -- R01 GM089763/GM/NIGMS NIH HHS/ -- R01 GM089763-01/GM/NIGMS NIH HHS/ -- R01 GM089763-02/GM/NIGMS NIH HHS/ -- England -- Nature. 2011 Mar 3;471(7336):104-9. doi: 10.1038/nature09732.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21368833" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; *Apoptosis/drug effects ; Benzenesulfonates/pharmacology ; Biphenyl Compounds/pharmacology ; Cell Cycle Proteins/genetics/*metabolism ; Cell Line, Tumor ; F-Box Proteins/genetics/*metabolism ; Glycogen Synthase Kinase 3/metabolism ; Humans ; Mice ; Molecular Sequence Data ; Myeloid Cell Leukemia Sequence 1 Protein ; Niacinamide/analogs & derivatives ; Nitrophenols/pharmacology ; Phenylurea Compounds ; Phosphorylation ; Piperazines/pharmacology ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology ; Protein Binding/drug effects ; Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors/*chemistry/*metabolism ; Pyridines/pharmacology ; SKP Cullin F-Box Protein Ligases/*chemistry/*metabolism ; Sulfonamides/pharmacology ; Tumor Suppressor Proteins/deficiency/genetics/metabolism ; Ubiquitin-Protein Ligases/deficiency/genetics/*metabolism ; *Ubiquitination/drug effects
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2011-02-11
    Description: Telomere dysfunction activates p53-mediated cellular growth arrest, senescence and apoptosis to drive progressive atrophy and functional decline in high-turnover tissues. The broader adverse impact of telomere dysfunction across many tissues including more quiescent systems prompted transcriptomic network analyses to identify common mechanisms operative in haematopoietic stem cells, heart and liver. These unbiased studies revealed profound repression of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha and beta (PGC-1alpha and PGC-1beta, also known as Ppargc1a and Ppargc1b, respectively) and the downstream network in mice null for either telomerase reverse transcriptase (Tert) or telomerase RNA component (Terc) genes. Consistent with PGCs as master regulators of mitochondrial physiology and metabolism, telomere dysfunction is associated with impaired mitochondrial biogenesis and function, decreased gluconeogenesis, cardiomyopathy, and increased reactive oxygen species. In the setting of telomere dysfunction, enforced Tert or PGC-1alpha expression or germline deletion of p53 (also known as Trp53) substantially restores PGC network expression, mitochondrial respiration, cardiac function and gluconeogenesis. We demonstrate that telomere dysfunction activates p53 which in turn binds and represses PGC-1alpha and PGC-1beta promoters, thereby forging a direct link between telomere and mitochondrial biology. We propose that this telomere-p53-PGC axis contributes to organ and metabolic failure and to diminishing organismal fitness in the setting of telomere dysfunction.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3741661/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3741661/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sahin, Ergun -- Colla, Simona -- Liesa, Marc -- Moslehi, Javid -- Muller, Florian L -- Guo, Mira -- Cooper, Marcus -- Kotton, Darrell -- Fabian, Attila J -- Walkey, Carl -- Maser, Richard S -- Tonon, Giovanni -- Foerster, Friedrich -- Xiong, Robert -- Wang, Y Alan -- Shukla, Sachet A -- Jaskelioff, Mariela -- Martin, Eric S -- Heffernan, Timothy P -- Protopopov, Alexei -- Ivanova, Elena -- Mahoney, John E -- Kost-Alimova, Maria -- Perry, Samuel R -- Bronson, Roderick -- Liao, Ronglih -- Mulligan, Richard -- Shirihai, Orian S -- Chin, Lynda -- DePinho, Ronald A -- P30 DK046200/DK/NIDDK NIH HHS/ -- P30DK079638/DK/NIDDK NIH HHS/ -- R01 CA084628/CA/NCI NIH HHS/ -- R01 DK035914/DK/NIDDK NIH HHS/ -- R01 DK056690/DK/NIDDK NIH HHS/ -- R01 DK063356/DK/NIDDK NIH HHS/ -- R01 DK089185/DK/NIDDK NIH HHS/ -- U24 DK-59635/DK/NIDDK NIH HHS/ -- England -- Nature. 2011 Feb 17;470(7334):359-65. doi: 10.1038/nature09787. Epub 2011 Feb 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21307849" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/biosynthesis ; Aging/metabolism/pathology ; Animals ; Cardiomyopathies/chemically induced/metabolism/pathology/physiopathology ; Cell Proliferation ; DNA, Mitochondrial/analysis ; Doxorubicin/toxicity ; Gluconeogenesis ; Hematopoietic Stem Cells/metabolism/pathology ; Liver/cytology/metabolism ; Mice ; Mitochondria/*metabolism/*pathology ; Myocardium/cytology/metabolism ; RNA/genetics ; Reactive Oxygen Species/metabolism ; Telomerase/deficiency/genetics ; Telomere/enzymology/genetics/*metabolism/*pathology ; Transcription Factors/antagonists & inhibitors/metabolism ; Tumor Suppressor Protein p53/deficiency/genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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