CiteULike: Author D'Amelio

Regulation of autophagy by cytoplasmic p53.

Ezgi Tasdemir — 2008-05-09T20:16:01-00:00

Nature cell biology (4 May 2008)

Multiple cellular stressors, including activation of the tumour suppressor p53, can stimulate autophagy. Here we show that deletion, depletion or inhibition of p53 can induce autophagy in human, mouse and nematode cells subjected to knockout, knockdown or pharmacological inhibition of p53. Enhanced autophagy improved the survival of p53-deficient cancer cells under conditions of hypoxia and nutrient depletion, allowing them to maintain high ATP levels. Inhibition of p53 led to autophagy in enucleated cells, and cytoplasmic, not nuclear, p53 was able to repress the enhanced autophagy of p53(-/-) cells. Many different inducers of autophagy (for example, starvation, rapamycin and toxins affecting the endoplasmic reticulum) stimulated proteasome-mediated degradation of p53 through a pathway relying on the E3 ubiquitin ligase HDM2. Inhibition of p53 degradation prevented the activation of autophagy in several cell lines, in response to several distinct stimuli. These results provide evidence of a key signalling pathway that links autophagy to the cancer-associated dysregulation of p53.

Nonapoptotic role for Apaf-1 in the DNA damage checkpoint.

Y Zermati — 2008-01-12T19:23:54-00:00

Mol Cell, Vol. 28, No. 4. (30 November 2007), pp. 624-637.

Apaf-1 is an essential factor for cytochrome c-driven caspase activation during mitochondrial apoptosis but has also an apoptosis-unrelated function. Knockdown of Apaf-1 in human cells, knockout of apaf-1 in mice, and loss-of-function mutations in the Caenorhabditis elegans apaf-1 homolog ced-4 reveal the implication of Apaf-1/CED-4 in DNA damage-induced cell-cycle arrest. Apaf-1 loss compromised the DNA damage checkpoints elicited by ionizing irradiation or chemotherapy. Apaf-1 depletion reduced the activation of the checkpoint kinase Chk1 provoked by DNA damage, and knockdown of Chk1 abrogated the Apaf-1-mediated cell-cycle arrest. Nuclear translocation of Apaf-1, induced in vitro by exogenous DNA-damaging agents, correlated in non-small cell lung cancer (NSCLC) with the endogenous activation of Chk-1, suggesting that this pathway is clinically relevant. Hence, Apaf-1 exerts two distinct, phylogenetically conserved roles in response to mitochondrial membrane permeabilization and DNA damage. These data point to a role for Apaf-1 as a bona fide tumor suppressor.

N-linked glycosylation of the liver cancer biomarker GP73.

Pamela A Norton — 2007-11-16T16:52:14-00:00

J Cell Biochem (14 November 2007)

The association between elevated circulating levels of GP73 (and fucosylated GP73 in particular) and hepatocellular carcinoma suggests that a thorough analysis of the extent of GP73 glycosylation is warranted. Detailed analysis of the glycosylation patterns of such low abundance proteins are hampered by technical difficulties. Using conventional lectin affinity chromatography, we have established that three quarters of the GP73 secreted from a cell line derived from HCC is fucosylated. Using mass spectrometry, we have established that at least two of three potential sites of N-linked glycosylation are occupied on most molecules of GP73 secreted from cultured hepatoma cells. Furthermore, the oligosaccharides added to recombinant GP73 resemble those present in the bulk of secreted protein, mostly bi-antennary with core fucose, with a smaller fraction of tri- and tetra-antennary structures. The frequency of fucosylation observed on the recombinant protein agrees well with the pattern of lectin binding of the endogenous secreted protein. Finally, we have developed a method to interrogate the glycans added to either the near full length protein or at a particular sequon, providing proof of concept that a small peptide embedded in a heterologous context can preserve both fucosylation and a high level of branching of oligosaccharides added. J. Cell. Biochem. (c) 2007 Wiley-Liss, Inc.

Height as a potential indicator of early life events predicting Parkinson's disease: A case-control study.

Paolo Ragonese — 2007-09-18T13:56:48-00:00

Mov Disord (12 September 2007)

Aim of this study was to investigate the relationship between height in young adult age and Parkinson's disease (PD) risk. We included 266 persons affected by idiopathic PD. Patients were matched by age and sex to 266 controls by a random selection from the municipality of residence. We collected information about height preceding PD from official documents where these characteristics referred to young adult age (nearly 30 years). We compared height in cases and controls by calculating differences in mean distribution and by chi(2) analyses. Crude and adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated by logistic regression models. Mean height was significantly lower in persons affected by PD compared to controls (P = 0.03). Difference was significant only in men (P = 0.001). Logistic regression models showed an inverse association between height and PD (OR 0.35; CI 0.16, 0.79; P < 0.01 comparing individuals in the highest percentiles of height with those in the lowest). Our results indicate an association between height and PD in men. Considering that dopamine sensitivity in the hypothalamic-pituitary axis is related to adult height, our findings suggest a relationship between PD and factors modulating somatic growth early in life. (c) 2007 Movement Disorder Society.