Protein-Serine-Threonine Kinases

Publication Title: 
Experimental Cell Research

Cellular senescence is a state of irreversible cell cycle arrest in which normal cells at the end of their lifespan fail to enter into DNA synthesis upon serum or growth factor stimulation. We examined whether proteins required for G1/S cell cycle progression were irreversibly down-regulated in senescent human fibroblasts. Both the 44- and 42-kDa forms of the MAP-kinase protein were expressed at similar levels in young and senescent cells.

Author(s): 
Afshari, C. A.
Vojta, P. J.
Annab, L. A.
Futreal, P. A.
Willard, T. B.
Barrett, J. C.
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: 
Oncogene

Replicative senescence is thought to be a significant barrier to human tumorigenesis, which in human fibroblasts, and many other cell types, can be overcome experimentally by combined loss of function of p53 and Rb 'pathways'. To avoid the confounding pleiotropic effects of HPVE7 frequently used in such studies, here we have employed retroviral vectors over-expressing CDK4 or CDK6 as a more representative model of naturally-occurring mutations targeting the Rb pathway.

Author(s): 
Morris, Mark
Hepburn, Peter
Wynford-Thomas, David
Publication Title: 
Investigative Ophthalmology & Visual Science

PURPOSE: To investigate the migratory and contractile behavior of isolated human corneal fibroblasts in fibrillar collagen matrices. METHODS: A telomerase-infected, extended-lifespan human corneal fibroblast cell line (HTK) was transfected by using a vector for enhanced green fluorescent protein (GFP)-alpha-actinin. Cells were plated at low density on top of or within 100-microm-thick fibrillar collagen lattices. After 18 hours to 7 days, time-lapse imaging was performed.

Author(s): 
Vishwanath, Mridula
Ma, Lisha
Otey, Carol A.
Jester, James V.
Petroll, W. Matthew
Publication Title: 
The EMBO journal

Telomere shortening in normal human cells causes replicative senescence, a p53-dependent growth arrest state, which is thought to represent an innate defence against tumour progression. However, although it has been postulated that critical telomere loss generates a 'DNA damage' signal, the signalling pathway(s) that alerts cells to short dysfunctional telomeres remains only partially defined.

Author(s): 
Gire, VÈronique
Roux, Pierre
Wynford-Thomas, David
Brondello, Jean-Marc
Dulic, Vjekoslav
Publication Title: 
Human Molecular Genetics

Autophagy is a highly regulated intracellular process involved in the turnover of most cellular constituents and in the maintenance of cellular homeostasis. It is well-established that the basal autophagic activity of living cells decreases with age, thus contributing to the accumulation of damaged macromolecules during aging. Conversely, the activity of this catabolic pathway is required for lifespan extension in animal models such as Caenorhabditis elegans and Drosophila melanogaster.

Author(s): 
MariÒo, Guillermo
Ugalde, Alejandro P.
Salvador-Montoliu, Natalia
Varela, Ignacio
QuirÛs, Pedro M.
CadiÒanos, Juan
van der Pluijm, Ingrid
Freije, JosÈ M. P.
LÛpez-OtÌn, Carlos
Publication Title: 
Rejuvenation Research

Can we extend human lifespan? Do we need to regulate lifestyle choices or can we simply pop a pill to make us live longer? These are questions raised by two new studies demonstrating significant lifespan extension in mice fed the drug rapamycin in their diet and in calorically restricted rhesus monkeys.

Author(s): 
Cox, Lynne S.
Publication Title: 
The EMBO journal

Senescence is an irreversible cell-cycle arrest that is elicited by a wide range of factors, including replicative exhaustion. Emerging evidences suggest that cellular senescence contributes to ageing and acts as a tumour suppressor mechanism. To identify novel genes regulating senescence, we performed a loss-of-function screen on normal human diploid fibroblasts. We show that downregulation of the AMPK-related protein kinase 5 (ARK5 or NUAK1) results in extension of the cellular replicative lifespan.

Author(s): 
Humbert, Nicolas
Navaratnam, Naveenan
Augert, Arnaud
Da Costa, Marco
Martien, SÈbastien
Wang, Jing
Martinez, Dolores
Abbadie, Corinne
Carling, David
de Launoit, Yvan
Gil, Jesus
Bernard, David
Publication Title: 
Current Opinion in Drug Discovery & Development

TOR (target of rapamycin) is a serine-threonine protein kinase that is conserved across a diverse range of species from fungi to mammals. The signaling pathway that is anchored by TOR is also conserved across species. In mammals, mTOR integrates growth factor, amino acid, nutrient and energy sensing signals, and thus plays a major role in cell growth and proliferation, protein synthesis and autophagy.

Author(s): 
Sudarsanam, Sucha
Johnson, Dale E.
Publication Title: 
Aging Cell

Dietary restriction (DR) is a robust nongenetic, nonpharmacological intervention that is known to increase active and healthy lifespan in a variety of species. Despite a variety of differences in the protocols and the way DR is carried out in different species, conserved relationships are emerging among multiple species. 2009 saw the field of DR mature with important mechanistic insights from multiple species. A report of lifespan extension in rapamycin-treated mice suggested that the TOR pathway, a conserved mediator of DR in invertebrates, may also be critical to DR effects in mammals.

Author(s): 
Katewa, Subhash D.
Kapahi, Pankaj

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