DNA-Binding Proteins

Publication Title: 
The EMBO journal

Telomere loss has been proposed as a mechanism for counting cell divisions during aging in normal somatic cells. How such a mitotic clock initiates the intracellular signalling events that culminate in G1 cell cycle arrest and senescence to restrict the lifespan of normal human cells is not known. We investigated the possibility that critically short telomere length activates a DNA damage response pathway involving p53 and p21(WAF1) in aging cells.

Author(s): 
Vaziri, H.
West, M. D.
Allsopp, R. C.
Davison, T. S.
Wu, Y. S.
Arrowsmith, C. H.
Poirier, G. G.
Benchimol, S.
Publication Title: 
International Journal of Oncology

Retroviral infection of hTERT, the catalytic component of telomerase, into BJ fibroblasts (population doubling 28) resulted in reconstitution of telomerase activity, telomere maintenance, and extension of in vitro lifespan. The hTERT-infected cells also exhibited increased growth rate and colony forming efficiency relative to controls, while remaining contact-inhibited and maintaining a p53-mediated damage response following gamma-irradiation.

Author(s): 
Forsythe, Heidi L.
Elmore, Lynne W.
Jensen, Keith O.
Landon, Melissa R.
Holt, Shawn E.
Publication Title: 
Cancer Research

The vast majority of breast cancers are carcinomas that arise from mammary epithelial cells (MECs). One of the key early events in tumorigenic transformation is the ability of cells to overcome replicative senescence. However, the precise genetic changes that are responsible for this event in MECs is largely unknown. Here, we report that Bmi-1, originally identified as a c-Myc cooperating oncoprotein, can bypass senescence, extend the replicative life span, and immortalize MECs. Furthermore, Bmi-1 was overexpressed in immortal MECs and several breast cancer cell lines.

Author(s): 
Dimri, Goberdhan P.
Martinez, Jose-Luis
Jacobs, Jacqueline J. L.
Keblusek, Petra
Itahana, Koji
Van Lohuizen, Maarten
Campisi, Judith
Wazer, David E.
Band, Vimla
Publication Title: 
Experimental Cell Research

The lifespan of human foreskin fibroblasts (HFF5), cultured under standard in vitro conditions (including ambient atmospheric oxygen tension), was extended slightly by expression of exogenous mortalin (mot-2)/mthsp70/Grp75, but not by the catalytic subunit of telomerase, hTERT. Together, mot-2 and hTERT permitted bypass of senescence, a substantial extension of lifespan, and possibly immortalization. This is the first demonstration that mot-2 and telomerase can cooperate in the immortalization process.

Author(s): 
Kaul, Sunil C.
Yaguchi, Tomoko
Taira, Kazunari
Reddel, Roger R.
Wadhwa, Renu
Publication Title: 
Molecular and Cellular Biochemistry

Hexavalent chromium (Cr(VI)) is a metal of increasing public health concern, as exposure to it is widespread and it is a well-established cause of human bronchial carcinomas and fibrosarcomas. The water-insoluble Cr(VI) salts are potent carcinogens compared to the water soluble salts; yet the genotoxic mechanisms of both may be mediated by soluble Cr(VI) ions. Currently, these mechanisms are poorly understood.

Author(s): 
Wise, Sandra S.
Elmore, Lynne W.
Holt, Shawn E.
Little, Jennifer E.
Antonucci, Peter G.
Bryant, Bronwyn H.
Wise, John Pierce
Publication Title: 
Nature

Calorie restriction extends lifespan in organisms ranging from yeast to mammals. In yeast, the SIR2 gene mediates the life-extending effects of calorie restriction. Here we show that the mammalian SIR2 orthologue, Sirt1 (sirtuin 1), activates a critical component of calorie restriction in mammals; that is, fat mobilization in white adipocytes. Upon food withdrawal Sirt1 protein binds to and represses genes controlled by the fat regulator PPAR-gamma (peroxisome proliferator-activated receptor-gamma), including genes mediating fat storage.

Author(s): 
Picard, FrÈdÈric
Kurtev, Martin
Chung, Namjin
Topark-Ngarm, Acharawan
Senawong, Thanaset
Machado De Oliveira, Rita
Leid, Mark
McBurney, Michael W.
Guarente, Leonard
Publication Title: 
Aging Cell

Fetal cardiomyocytes have been proposed as a potential source of cell-based therapy for heart failure. This study examined cellular senescence in cultured human fetal ventricular cardiomyocytes (HFCs). HFCs were isolated and identified by immunocytochemistry and RT-PCR. Cells were found to senesce after 20-25 population doublings, as determined by growth arrest, morphological changes and senescence-associated beta-galactosidase activity. Using the telomeric repeat amplification protocol assay, telomerase activity was undetectable in primary HFCs.

Author(s): 
Ball, Andrew J.
Levine, Fred
Publication Title: 
Oncogene

Many degenerative diseases that occur with aging, as well as premature aging syndromes, are characterized by presenting cells with critically short telomeres. Telomerase reintroduction is envisioned as a putative therapy for diseases characterized by telomere exhaustion. K5-mTert transgenic mice overexpress telomerase in a wide spectrum of tissues. These mice have a higher incidence of both induced and spontaneous tumors, resulting in increased mortality during the first year of life.

Author(s): 
Gonz·lez-Su·rez, Eva
Geserick, Christoph
Flores, Juana M.
Blasco, Maria A.
Publication Title: 
The Journal of Biological Chemistry

In lower organisms, increased expression of the NAD-dependent deacetylase Sir2 augments lifespan. The mechanism through which this life extension is mediated remains incompletely understood. Here we have examined the cellular effects of overexpression of SIRT1, the closest mammalian ortholog of Sir2. In PC12 cells, increased expression of the NAD-dependent deacetylase SIRT1 reduces cellular oxygen consumption by approximately 25%. We further demonstrate that SIRT1 expression can alter the transcriptional activity of the mitochondrial biogenesis coactivator PGC-1alpha.

Author(s): 
Nemoto, Shino
Fergusson, Maria M.
Finkel, Toren
Publication Title: 
Blood

To obtain the large amount of T cells required for adoptive immunotherapy in a clinical setting, T-cell lifespan extension by human telomerase reverse transcriptase (hTERT) transduction is of particular interest. However, constitutive expression of hTERT is associated with malignant transformation and thus warrants a detailed evaluation of the safety of hTERT-transduced T cells before clinical application.

Author(s): 
Schreurs, Marco W. J.
Hermsen, Mario A. J. A.
Geltink, Ramon I. Klein
Scholten, Kirsten B. J.
Brink, Antoinette A. T. P.
Kueter, Esther W. M.
Tijssen, Marianne
Meijer, Chris J. L. M.
Ylstra, Bauke
Meijer, Gerrit A.
Hooijberg, Erik

Pages

Subscribe to RSS - DNA-Binding Proteins