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  • 1
    Publication Date: 2015-05-02
    Description: Centrioles are ancient organelles that build centrosomes, the major microtubule-organizing centers of animal cells. Extra centrosomes are a common feature of cancer cells. To investigate the importance of centrosomes in the proliferation of normal and cancer cells, we developed centrinone, a reversible inhibitor of Polo-like kinase 4 (Plk4), a serine-threonine protein kinase that initiates centriole assembly. Centrinone treatment caused centrosome depletion in human and other vertebrate cells. Centrosome loss irreversibly arrested normal cells in a senescence-like G1 state by a p53-dependent mechanism that was independent of DNA damage, stress, Hippo signaling, extended mitotic duration, or segregation errors. In contrast, cancer cell lines with normal or amplified centrosome numbers could proliferate indefinitely after centrosome loss. Upon centrinone washout, each cancer cell line returned to an intrinsic centrosome number "set point." Thus, cells with cancer-associated mutations fundamentally differ from normal cells in their response to centrosome loss.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764081/" 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/PMC4764081/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wong, Yao Liang -- Anzola, John V -- Davis, Robert L -- Yoon, Michelle -- Motamedi, Amir -- Kroll, Ashley -- Seo, Chanmee P -- Hsia, Judy E -- Kim, Sun K -- Mitchell, Jennifer W -- Mitchell, Brian J -- Desai, Arshad -- Gahman, Timothy C -- Shiau, Andrew K -- Oegema, Karen -- GM074207/GM/NIGMS NIH HHS/ -- GM089970/GM/NIGMS NIH HHS/ -- GM103403/GM/NIGMS NIH HHS/ -- R01 GM089970/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Jun 5;348(6239):1155-60. doi: 10.1126/science.aaa5111. Epub 2015 Apr 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cellular and Molecular Medicine, Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA. ; Small Molecule Discovery Program, Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA. ; Department of Cell and Molecular Biology, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA. ; Small Molecule Discovery Program, Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA. koegema@ucsd.edu ashiau@ucsd.edu. ; Department of Cellular and Molecular Medicine, Ludwig Institute for Cancer Research, University of California, San Diego, La Jolla, CA 92093, USA. koegema@ucsd.edu ashiau@ucsd.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25931445" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line, Tumor ; Cell Proliferation ; Centrioles/*drug effects ; Humans ; Mice ; Piperazines/pharmacology ; Protein Kinase Inhibitors/chemistry/*pharmacology ; Protein-Serine-Threonine Kinases/*antagonists & inhibitors ; Pyrimidines/chemistry/*pharmacology ; Sulfones/chemistry/*pharmacology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
    Electronic Resource
    Electronic Resource
    Oxford, UK : Munksgaard International Publishers
    Journal of cutaneous pathology 30 (2003), S. 0 
    ISSN: 1600-0560
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background:  The aberrant expression of both the retinoblastoma and p53 tumor suppressor genes has been associated with more aggressive tumors, metastasis and lower survival.Methods:  We have evaluated immunohistochemically the expression of pRB in a panel of non-melanoma skin cancers containing p53 somatic mutations.Results:  Nuclear anti-p53 staining was detected in 18 (72%) differentiated squamous cell carcinomas, six (100%) undifferentiated squamous cell carcinomas and seven (28%) basal cell carcinomas. A correlation was observed between p53 expression and the proliferative activity of differentiated squamous cell carcinomas (P 〈 0.066), undifferentiated squamous cell carcinomas (P 〈 0.05) and basal cell carcinomas (P 〈 0.01). Tumors were selected for mutant p53 expression by PCR-directed DNA sequencing and pRB expression measured immunohistochemically. Anti-pRB reactivity was detected in the nuclei of basal and suprabasal layer cells of normal epidermis, and in the proliferative compartment of all the differentiated squamous cell carcinomas, and basal cell carcinomas. A correlation was observed between pRB expression and the proliferative activity of the differentiated squamous cell carcinomas (P 〈 0.01) and basal cell carcinomas (P 〈 0.025). However, anti-pRB reactivity was not detected in the six anti-p53 reactive undifferentiated squamous cell carcinomas.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1573-6903
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The yields of total and poly(A) RNA were examined in rabbit forebrains during an experimentally induced aluminum encephalopathy. Rabbits (35 day old) were injected intracranially with 13 μmole Al lactate and sacrificed 1, 3, 7, 10, or 12 days later. IRNA yields (total RNA minus transfer RNA) were not significantly altered during the encephalopathy. Poly(A) RNA yields, assayed by oligo(dT)-cellulose fractionation and by a [3H]poly(U) hybridization assay on IRNA, were increased significantly by the end of the asymptomatic stage of the encephalopathy (7 days post-Al injection). The increase in messenger RNA population may represent either a compensatory response to cell damage induced by aluminum or the accumulation of messager RNA for proteins directly related to the expression of aluminum toxicity.
    Type of Medium: Electronic Resource
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