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  • 1
    Abstract: We have recently identified lens epithelium-derived growth factor (LEDGF/p75, also known as PSIP1) as a component of the homologous recombination DNA repair machinery. Through its Pro-Trp-Trp-Pro (PWWP) domain, LEDGF/p75 binds to histone marks associated with active transcription and promotes DNA end resection by recruiting DNA endonuclease retinoblastoma-binding protein 8 (RBBP8/CtIP) to broken DNA ends. Here we show that the structurally related PWWP domain-containing protein, hepatoma-derived growth factor-related protein 2 (HDGFRP2), serves a similar function in homologous recombination repair. Its depletion compromises the survival of human U2OS osteosarcoma and HeLa cervix carcinoma cells and impairs the DNA damage-induced phosphorylation of replication protein A2 (RPA2) and the recruitment of DNA endonuclease RBBP8/CtIP to DNA double strand breaks. In contrast to LEDGF/p75, HDGFRP2 binds preferentially to histone marks characteristic for transcriptionally silent chromatin. Accordingly, HDGFRP2 is found in complex with the heterochromatin-binding chromobox homologue 1 (CBX1) and Pogo transposable element with ZNF domain (POGZ). Supporting the functionality of this complex, POGZ-depleted cells show a similar defect in DNA damage-induced RPA2 phosphorylation as HDGFRP2-depleted cells. These data suggest that HDGFRP2, possibly in complex with POGZ, recruits homologous recombination repair machinery to damaged silent genes or to active genes silenced upon DNA damage.
    Type of Publication: Journal article published
    PubMed ID: 26721387
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  • 2
    Publication Date: 2014-03-29
    Description: Akt, also known as protein kinase B, plays key roles in cell proliferation, survival and metabolism. Akt hyperactivation contributes to many pathophysiological conditions, including human cancers, and is closely associated with poor prognosis and chemo- or radiotherapeutic resistance. Phosphorylation of Akt at S473 (ref. 5) and T308 (ref. 6) activates Akt. However, it remains unclear whether further mechanisms account for full Akt activation, and whether Akt hyperactivation is linked to misregulated cell cycle progression, another cancer hallmark. Here we report that Akt activity fluctuates across the cell cycle, mirroring cyclin A expression. Mechanistically, phosphorylation of S477 and T479 at the Akt extreme carboxy terminus by cyclin-dependent kinase 2 (Cdk2)/cyclin A or mTORC2, under distinct physiological conditions, promotes Akt activation through facilitating, or functionally compensating for, S473 phosphorylation. Furthermore, deletion of the cyclin A2 allele in the mouse olfactory bulb leads to reduced S477/T479 phosphorylation and elevated cellular apoptosis. Notably, cyclin A2-deletion-induced cellular apoptosis in mouse embryonic stem cells is partly rescued by S477D/T479E-Akt1, supporting a physiological role for cyclin A2 in governing Akt activation. Together, the results of our study show Akt S477/T479 phosphorylation to be an essential layer of the Akt activation mechanism to regulate its physiological functions, thereby providing a new mechanistic link between aberrant cell cycle progression and Akt hyperactivation in cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4076493/" 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/PMC4076493/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Pengda -- Begley, Michael -- Michowski, Wojciech -- Inuzuka, Hiroyuki -- Ginzberg, Miriam -- Gao, Daming -- Tsou, Peiling -- Gan, Wenjian -- Papa, Antonella -- Kim, Byeong Mo -- Wan, Lixin -- Singh, Amrik -- Zhai, Bo -- Yuan, Min -- Wang, Zhiwei -- Gygi, Steven P -- Lee, Tae Ho -- Lu, Kun-Ping -- Toker, Alex -- Pandolfi, Pier Paolo -- Asara, John M -- Kirschner, Marc W -- Sicinski, Piotr -- Cantley, Lewis -- Wei, Wenyi -- 2P01CA120964/CA/NCI NIH HHS/ -- 5T32HL007893/HL/NHLBI NIH HHS/ -- CA177910/CA/NCI NIH HHS/ -- GM089763/GM/NIGMS NIH HHS/ -- GM094777/GM/NIGMS NIH HHS/ -- P01 CA120964/CA/NCI NIH HHS/ -- R01 CA132740/CA/NCI NIH HHS/ -- R01 CA167677/CA/NCI NIH HHS/ -- R01 CA177910/CA/NCI NIH HHS/ -- R01 GM041890/GM/NIGMS NIH HHS/ -- R01 GM089763/GM/NIGMS NIH HHS/ -- R01 GM094777/GM/NIGMS NIH HHS/ -- R01 HL111430/HL/NHLBI NIH HHS/ -- R01CA132740/CA/NCI NIH HHS/ -- S10 OD010612/OD/NIH HHS/ -- T32 HL007893/HL/NHLBI NIH HHS/ -- England -- Nature. 2014 Apr 24;508(7497):541-5. doi: 10.1038/nature13079. Epub 2014 Mar 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. ; 1] Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA [2] Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA [2] Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA [3] Cancer Genetics Program and Division of Genetics, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA. ; Division of Gerontology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA. ; Cell Signaling Technology, Danvers, Massachusetts 01923, USA. ; Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA. ; 1] Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA [2] The Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou 215123, China (Z.W.); Cancer Center at Weill Cornell Medical College and NewYork-Presbyterian Hospital, New York, New York 10065, USA (L.C.). ; Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA [2] Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA [3] The Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, the First Affiliated Hospital, Soochow University, Suzhou 215123, China (Z.W.); Cancer Center at Weill Cornell Medical College and NewYork-Presbyterian Hospital, New York, New York 10065, USA (L.C.).〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24670654" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis/genetics ; Cell Cycle/*physiology ; Cell Proliferation ; Cyclin A2/metabolism ; Cyclin-Dependent Kinase 2/metabolism ; Embryonic Stem Cells/cytology/metabolism ; Enzyme Activation ; Male ; Mice ; Multiprotein Complexes/metabolism ; Neoplasms/enzymology/pathology ; Olfactory Bulb/cytology/enzymology/metabolism ; Oncogene Protein v-akt/chemistry/metabolism ; Phosphorylation ; Phosphoserine/metabolism ; Phosphothreonine/metabolism ; Proto-Oncogene Proteins c-akt/*chemistry/*metabolism ; TOR Serine-Threonine Kinases/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    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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