Biomedical subjects

A Gutsmann

Publications and source records attributed to A Gutsmann.

4 recordsLinked to original sources

PubMed1996

Effect of caloric restriction on the expression of heat shock protein 70 and the activation of heat shock transcription factor 1.

The regulation of heat shock protein 70 (hsp70) expression is an excellent example of a cellular mechanism that has evolved to protect all living organisms from various types of physiological stresses; therefore, the reported age-related alterations in the ability of cells to express hsp70 in response to stress could seriously compromise the ability of a senescent organism in respond to changes in its environment. Because caloric restriction (CR) is the only experimental manipulation known to retard aging and increase the survival of rodents, it was of interest to analyze the effect of CR on the age-related alteration in the induction of hsp70 expression in rat hepatocytes. The effect of CR on the nuclear transcription of hsp70 gene in rat hepatocytes in response to various levels of heat shock was determined, and it was found that the age-related decline in the transcription of hsp70 at all temperatures studied was reversed by CR. Because the heat shock transcription factor (HSF) mediates the heat-induced transcription of hsp70, the effect of CR on the induction of HSF binding activity by heat shock was studied and found to arise from HSF1, which has been shown to be involved in the induction of HSF binding activity in other cell types. The age-related decrease in the induction of HSF1 binding activity in rat hepatocytes was reversed by CR, and did not appear to be due to an accumulation of inhibitory molecules with age. Interestingly, the level of HSF1 protein was significantly higher in hepatocytes isolated from old rats fed ad libitum compared to hepatocytes obtained from rats fed the CR diet even though the levels of HSF1 binding activity were lower for hepatocytes isolated from the old rats fed ad libitum. The levels of the mRNA transcript for HSF1 was not significantly altered by age or CR. Thus, the changes in HSF1 binding activity with age and CR do not arise from changes in the level of HSF1 protein available for activation.

Age Factors↗

PubMed1994

Hsp70 and aging.

An alteration in the ability of cells to express heat shock proteins could be physiologically important in aging because all living organisms show a reduced ability to respond to stress with increasing age. Using hepatocytes freshly isolated from young adult and old rats, we have shown that the induction of hsp70 expression by heat shock is reduced approximately 50% with age. The decrease in hsp70 expression occurs at the level of transcription and appears to arise from a defect in the heat shock transcription factor. Other investigators have also shown that the induction of hsp70 expression by heat shock as well as other stresses declines significantly with age in a variety of tissues from rats as well as mononuclear cells from human subjects. In addition, a decrease in the inducibility of hsp70 is observed with cell senescence in cultured cells. Therefore, it appears that a reduced ability to express hsp70 in response to stress may be a common phenomenon underlying the aging process.

Aging↗

PubMed1994

The heat shock transcription factor in liver exists in a form that has DNA binding activity but no transcriptional activity.

The binding activity of the heat shock transcription factor (HSF) to the heat shock element (HSE) is observed in non-stressed liver and freshly isolated hepatocytes when the expression of hsp70 is undetectable. HSF binding activity in non-stressed liver/hepatocytes is specific for HSE and similar to the HSF binding activity observed in heat shocked hepatocytes that is associated with hsp70 transcription. However, the HSF binding activity in non-stressed and heat shock cells can be distinguished on the basis of the thermal stability in vitro. The HSE binding activity of cell extracts isolated from non-stressed liver/hepatocytes was lost rapidly when the extracts were incubated at 37 degrees C. In contrast, the HSF binding activity of cell extracts isolated from heat shocked hepatocytes was relatively stable at 37 degrees C. Based on our observations, we propose that the activation of HSF is a multistep process that involves a change in conformation after oligomerization and the acquisition of DNA binding to a form that is more thermostable and is associated with increased hsp70 transcription.

Animals↗

PubMed1994

Heterozygous Rb-1 delta 20/+mice are predisposed to tumors of the pituitary gland with a nearly complete penetrance.

Humans with a germline mutation of the RB gene are predisposed to retinoblastoma with a 90% penetrance and are at higher risk for other rare tumors. We have established a mouse strain carrying a germ-line mutation of the Rb-1 gene. Here we describe a nearly 100% incidence of spontaneous pituitary tumors which arise in Rb-1 heterozygous mice from ages 2 to 11 months. Histological and immunological analysis indicate that these tumors originate from the intermediate lobe of the pituitary gland, which is a vestigial structure in adult humans. Progression of the tumors can be followed by the elevated level of a specific proteolytic product of pro-opiomelanocortin prohormone, alpha-melanocyte stimulating hormone, in the circulating blood of the tumor-bearing animals. Multiple foci are frequently seen in the tiny intermediate lobe of the pituitary gland which contains approximately 1.5 x 10(5) cells. The tumor tissues invariably lose expression of full-length Rb protein due to loss of the single wild-type Rb-1 allele. The Rb knock out mouse strain provides a unique model for addressing tissue-specific tumor predisposition by inactivation of a ubiquitously expressed tumor suppressor gene.

Age Factors↗