Transcriptional Activation

Publication Title: 
Oncogene

Normal human breast epithelial cells were transfected with expression vectors containing the p53 gene mutated at either codon 143, 175, 248 or 273, or by infection with a recombinant retroviral vector containing the p53 gene mutated at codons 143, 175, 248, or 273. The breast epithelial cells were monitored for extension of in vitro lifespan and immortalization. Expression of some, but not all, p53 mutants resulted in an extension of in vitro lifespan.

Author(s): 
Gollahon, L. S.
Shay, J. W.
Publication Title: 
The EMBO journal

The yeast Sir2 protein mediates chromatin silencing through an intrinsic NAD-dependent histone deacetylase activity. Sir2 is a conserved protein and was recently shown to regulate lifespan extension both in budding yeast and worms. Here, we show that SIRT1, the human Sir2 homolog, is recruited to the promyelocytic leukemia protein (PML) nuclear bodies of mammalian cells upon overexpression of either PML or oncogenic Ras (Ha-rasV12). SIRT1 binds and deacetylates p53, a component of PML nuclear bodies, and it can repress p53-mediated transactivation.

Author(s): 
Langley, Emma
Pearson, Mark
Faretta, Mario
Bauer, Uta-Maria
Frye, Roy A.
Minucci, Saverio
Pelicci, Pier Giuseppe
Kouzarides, Tony
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: 
Cancer Biology & Therapy

Studies were conducted to directly test whether the introduction of telomerase protects cancer-prone human mammary epithelial cells from chromosomal instability and spontaneous immortalization. Using a model for Li Fraumeni Syndrome (LFS), infection of human telomerase resulted in maintenance of telomere lengths, extension of in vitro lifespan, and prevention of spontaneous immortalization.

Author(s): 
Elmore, Lynne W.
Turner, Kristi C.
Gollahon, Lauren S.
Landon, Melissa R.
Jackson-Cook, Colleen K.
Holt, Shawn E.
Publication Title: 
Toxicology and Applied Pharmacology

The ID (inhibitor of differentiation or DNA binding) helix-loop-helix proteins are important mediators of cellular differentiation and proliferation in a variety of cell types through regulation of gene expression. Overexpression of the ID proteins in normal human keratinocytes results in extension of culture lifespan, indicating that these proteins are important for epidermal differentiation. Our hypothesis is that the ID proteins are targets of the retinoic acid signaling pathway in keratinocytes.

Author(s): 
Villano, C. M.
White, L. A.
Publication Title: 
Molecular genetics and genomics: MGG

The heat shock factor (HSF), a protein evolutionarily conserved from yeasts to human, regulates the expression of a set of proteins called heat shock proteins (HSPs), many of which function as molecular chaperones. In Saccharomyces cerevisiae, the HSF binds to the 5' upstream region of YGR146C and activates its transcription. YGR146C encodes a functional homolog of ecl1 (+), ecl2 (+), and ecl3 (+) of Schizosaccharomyces pombe. At present, these Ecl1 family genes, which are extenders of chronological lifespan, have been identified only in fungi groups.

Author(s): 
Ohtsuka, Hokuto
Azuma, Kenko
Murakami, Hiroshi
Aiba, Hirofumi
Publication Title: 
PLoS genetics

Aging is characterized by the accumulation of damaged cellular macromolecules caused by declining repair and elimination pathways. An integral component employed by cells to counter toxic protein aggregates is the conserved ubiquitin/proteasome system (UPS). Previous studies have described an age-dependent decline of proteasomal function and increased longevity correlates with sustained proteasome capacity in centenarians and in naked mole rats, a long-lived rodent. Proof for a direct impact of enhanced proteasome function on longevity, however, is still lacking.

Author(s): 
Kruegel, Undine
Robison, Brett
Dange, Thomas
Kahlert, G¸nther
Delaney, Joe R.
Kotireddy, Soumya
Tsuchiya, Mitsuhiro
Tsuchiyama, Scott
Murakami, Christopher J.
Schleit, Jennifer
Sutphin, George
Carr, Daniel
Tar, Krisztina
Dittmar, Gunnar
Kaeberlein, Matt
Kennedy, Brian K.
Schmidt, Marion
Publication Title: 
Lipids in Health and Disease

BACKGROUND: Lifestyle factors and pharmacological compounds activate genetic mechanisms that influence the development of atherosclerotic and other diseases. This article reviews studies on natural and pharmacological gene activation that promotes health and enhances longevity. RESULTS: Living habits including healthy diet and regular physical activity, and pharmacotherapy, upregulate genes encoding enzymes and apolipoprotein and ATP-binding cassette transporters, acting in metabolic processes that promote health and increase survival.

Author(s): 
Luoma, Pauli V.
Publication Title: 
Proceedings of the National Academy of Sciences of the United States of America

Forkhead box class O 3a (FOXO3a) is a transcription factor and tumor suppressor linked to longevity that determines cell fate through activating transcription of cell differentiation, survival, and apoptotic genes. Recruitment of the coactivator CBP/p300 is a crucial step in transcription, and we revealed that in addition to conserved region 3 (CR3) of FOXO3a, the C-terminal segment of CR2 (CR2C) binds CBP/p300 and contributes to transcriptional activity.

Author(s): 
Wang, Feng
Marshall, Christopher B.
Yamamoto, Kazuo
Li, Guang-Yao
Gasmi-Seabrook, GeneviËve M. C.
Okada, Hitoshi
Mak, Tak W.
Ikura, Mitsuhiko
Publication Title: 
Genes & Development

Alterations in the architecture and dynamics of the nuclear lamina have a causal role in normal and accelerated aging through both cell-autonomous and systemic mechanisms. However, the precise nature of the molecular cues involved in this process remains incompletely defined. Here we report that the accumulation of prelamin A isoforms at the nuclear lamina triggers an ATM- and NEMO-dependent signaling pathway that leads to NF-?B activation and secretion of high levels of proinflammatory cytokines in two different mouse models of accelerated aging (Zmpste24(-/-) and Lmna(G609G/G609G) mice).

Author(s): 
Osorio, Fernando G.
B·rcena, Clea
Soria-Valles, Clara
Ramsay, Andrew J.
de Carlos, FÈlix
Cobo, Juan
Fueyo, Antonio
Freije, JosÈ M. P.
LÛpez-OtÌn, Carlos

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