Network


Latest external collaboration on country level. Dive into details by clicking on the dots.

Hotspot


Dive into the research topics where Marja Jäättelä is active.

Publication


Featured researches published by Marja Jäättelä.


Nature Reviews Molecular Cell Biology | 2001

Four deaths and a funeral : from caspases to alternative mechanisms

Marcel Leist; Marja Jäättelä

A single family of proteases, the caspases, has long been considered the pivotal executioner of all programmed cell death. However, recent findings of evolutionarily conserved, caspase-independent controlled death mechanisms have opened new perspectives on the biology of cell demise, with particular implications for neurobiology, cancer research and immunological processes.


Nature Reviews Cancer | 2005

Lysosomes and autophagy in cell death control

Guido Kroemer; Marja Jäättelä

Lysosomal hydrolases participate in the digestion of endocytosed and autophagocytosed material inside the lysosomal/autolysosomal compartment in acute cell death when released into the cytosol and in cancer progression following their release into the extracellular space. Lysosomal alterations are common in cancer cells. The increased expression and altered trafficking of lysosomal enzymes participates in tissue invasion, angiogenesis and sensitization to the lysosomal death pathway. But lysosomal heat-shock protein 70 locally prevents lysosomal-membrane permeabilization. Similarly, alterations in the autophagic compartment are linked to carcinogenesis and resistance to chemotherapy. Targeting these pathways might constitute a novel approach to cancer therapy.


FEBS Letters | 2007

The heat shock protein 70 family : Highly homologous proteins with overlapping and distinct functions

Mads Daugaard; Mikkel Rohde; Marja Jäättelä

The human heat shock protein 70 (Hsp70) family contains at least eight homologous chaperone proteins. Endoplasmatic reticulum and mitochondria have their specific Hsp70 proteins, whereas the remaining six family members reside mainly in the cytosol and nucleus. The requirement for multiple highly homologous although different Hsp70 proteins is still far from clear, but their individual and tissue‐specific expression suggests that they are assigned distinct biological tasks. This concept is supported by the fact that mice knockout for different Hsp70 genes display remarkably discrete phenotypes. Moreover, emerging data suggest that individual Hsp70 proteins can bring about non‐overlapping and chaperone‐independent functions essential for growth and survival of cancer cells. This review summarizes our present knowledge of the individual members of human Hsp70 family and elaborate on the functional differences between the cytosolic/nuclear representatives.


Nature Cell Biology | 2001

Heat-shock protein 70 antagonizes apoptosis-inducing factor.

Luigi Ravagnan; Sandeep Gurbuxani; Santos A. Susin; Carine Maisse; Eric Daugas; Naoufal Zamzami; Tak W. Mak; Marja Jäättelä; Josef M. Penninger; Carmen Garrido; Guido Kroemer

Heat-shock protein 70 (Hsp70) has been reported to block apoptosis by binding apoptosis protease activating factor-1 (Apaf-1), thereby preventing constitution of the apoptosome, the Apaf-1/cytochrome c/caspase-9 activation complex. Here we show that overexpression of Hsp70 protects Apaf-1−/− cells against death induced by serum withdrawal, indicating that Apaf-1 is not the only target of the anti-apoptotic action of Hsp70. We investigated the effect of Hsp70 on apoptosis mediated by the caspase-independent death effector apoptosis inducing factor (AIF), which is a mitochondrial intermembrane flavoprotein. In a cell-free system, Hsp70 prevented the AIF-induced chromatin condensation of purified nuclei. Hsp70 specifically interacted with AIF, as shown by ligand blots and co-immunoprecipitation. Cells overexpressing Hsp70 were protected against the apoptogenic effects of AIF targeted to the extramitochondrial compartment. In contrast, an anti-sense Hsp70 complementary DNA, which reduced the expression of endogenous Hsp70, increased sensitivity to the lethal effect of AIF. The ATP-binding domain of Hsp70 seemed to be dispensable for inhibiting cell death induced by serum withdrawal, AIF binding and AIF inhibition, although it was required for Apaf-1 binding. Together, our data indicate that Hsp70 can inhibit apoptosis by interfering with target proteins other than Apaf-1, one of which is AIF.


The EMBO Journal | 1998

Hsp70 exerts its anti‐apoptotic function downstream of caspase‐3‐like proteases

Marja Jäättelä; Dorte Wissing; Klaus Kokholm; Tuula Kallunki; Mikala Egeblad

The major heat shock protein, Hsp70, is an effective inhibitor of apoptosis. To study its mechanism of action, we created tumor cell lines with altered Hsp70 levels. The expression levels of Hsp70 in the cells obtained correlated well with their survival following treatments with tumor necrosis factor, staurosporine and doxorubicin. Surprisingly, the surviving Hsp70‐expressing cells responded to the apoptotic stimuli by activation of stress‐activated protein kinases, generation of free radicals, early disruption of mitochondrial transmembrane potential, release of cytochrome c from mitochondria and activation of caspase‐3‐like proteases in a manner essentially similar to that of the dying cells with low Hsp70 levels. However, Hsp70 inhibited late caspase‐dependent events such as activation of cytosolic phospholipase A2 and changes in nuclear morphology. Furthermore, Hsp70 conferred significant protection against cell death induced by enforced expression of caspase‐3. Thus, Hsp70 rescues cells from apoptosis later in the death signaling pathway than any known anti‐apoptotic protein, making it a tempting target for therapeutic interventions.


Cell Death & Differentiation | 2007

Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium.

Maria Høyer-Hansen; Marja Jäättelä

Eukaryotic cells respond to the accumulation of unfolded proteins in the endoplasmic reticulum (ER) either by unfolded protein response that leads to an increase in the capacity of the ER to fold its client proteins or by apoptosis when the function of ER cannot be restored. Emerging data now indicate that ER stress is also a potent inducer of macroautophagy, a process whereby eukaryotic cells recycle their macromolecules and organelles. Depending on the context, autophagy counterbalances ER stress-induced ER expansion, enhances cell survival or commits the cell to non-apoptotic death. Here, we discuss the signaling pathways linking ER stress to autophagy and possibilities for their clinical exploitation.


Cell Death & Differentiation | 2009

Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotes

Lorenzo Galluzzi; Stuart A. Aaronson; John M. Abrams; Emad S. Alnemri; David W. Andrews; Eric H. Baehrecke; Nicolas G. Bazan; Mikhail V. Blagosklonny; Klas Blomgren; Christoph Borner; Dale E. Bredesen; Catherine Brenner; Maria Castedo; John A. Cidlowski; Aaron Ciechanover; Gerald M. Cohen; V De Laurenzi; R De Maria; Mohanish Deshmukh; Brian David Dynlacht; Wafik S. El-Deiry; Richard A. Flavell; Simone Fulda; Carmen Garrido; Pierre Golstein; Marie Lise Gougeon; Douglas R. Green; Hinrich Gronemeyer; György Hajnóczky; J. M. Hardwick

Cell death is essential for a plethora of physiological processes, and its deregulation characterizes numerous human diseases. Thus, the in-depth investigation of cell death and its mechanisms constitutes a formidable challenge for fundamental and applied biomedical research, and has tremendous implications for the development of novel therapeutic strategies. It is, therefore, of utmost importance to standardize the experimental procedures that identify dying and dead cells in cell cultures and/or in tissues, from model organisms and/or humans, in healthy and/or pathological scenarios. Thus far, dozens of methods have been proposed to quantify cell death-related parameters. However, no guidelines exist regarding their use and interpretation, and nobody has thoroughly annotated the experimental settings for which each of these techniques is most appropriate. Here, we provide a nonexhaustive comparison of methods to detect cell death with apoptotic or nonapoptotic morphologies, their advantages and pitfalls. These guidelines are intended for investigators who study cell death, as well as for reviewers who need to constructively critique scientific reports that deal with cellular demise. Given the difficulties in determining the exact number of cells that have passed the point-of-no-return of the signaling cascades leading to cell death, we emphasize the importance of performing multiple, methodologically unrelated assays to quantify dying and dead cells.


Journal of Experimental Medicine | 2004

Heat Shock Protein 70 Promotes Cell Survival by Inhibiting Lysosomal Membrane Permeabilization

Jesper Nylandsted; Mads Gyrd-Hansen; Agnieszka Danielewicz; Nicole Fehrenbacher; Ulrik Lademann; Maria Høyer-Hansen; Ekkehard Weber; Gabriele Multhoff; Mikkel Rohde; Marja Jäättelä

Heat shock protein 70 (Hsp70) is a potent survival protein whose depletion triggers massive caspase-independent tumor cell death. Here, we show that Hsp70 exerts its prosurvival function by inhibiting lysosomal membrane permeabilization. The cell death induced by Hsp70 depletion was preceded by the release of lysosomal enzymes into the cytosol and inhibited by pharmacological inhibitors of lysosomal cysteine proteases. Accordingly, the Hsp70-mediated protection against various death stimuli in Hsp70-expressing human tumor cells as well as in immortalized Hsp70 transgenic murine fibroblasts occurred at the level of the lysosomal permeabilization. On the contrary, Hsp70 failed to inhibit the cytochrome c–induced, apoptosome-dependent caspase activation in vitro and Fas ligand–induced, caspase-dependent apoptosis in immortalized fibroblasts. Immunoelectron microscopy revealed that endosomal and lysosomal membranes of tumor cells contained Hsp70. Permeabilization of purified endo/lysosomes by digitonin failed to release Hsp70, suggesting that it is physically associated with the membranes. Finally, Hsp70 positive lysosomes displayed increased size and resistance against chemical and physical membrane destabilization. These data identify Hsp70 as the first survival protein that functions by inhibiting the death-associated permeabilization of lysosomes.


Annals of Medicine | 1999

Heat shock proteins as cellular lifeguards

Marja Jäättelä

Cells have developed complex ways to respond to various stresses. Interestingly, stresses such as heat, ischaemia and radiation can induce different cellular responses depending on their strength. While a mild stress induces a protective heat shock response, a more potent stress stimulus induces apoptosis and an even stronger one leads to necrosis. The heat shock or stress response, ie the synthesis of heat shock proteins (Hsps, stress proteins) in response to a mild stress, allows cells to adapt to gradual changes in their environment and to survive in otherwise lethal conditions. The ability of Hsps to protect cultured cells from both apoptosis and necrosis has been well demonstrated. Novel data suggest an important protective role for them also in vivo as they can protect heart and brain against ischaemia and lungs and liver against sepsis. Moreover, they can render tumours resistant to anticancer therapy. These and other cytoprotective effects of Hsps make them tempting targets for therapeutic interventions in several diseases.


Journal of Experimental Medicine | 2003

Lysosomal Membrane Permeabilization Induces Cell Death in a Mitochondrion-dependent Fashion

Patricia Boya; Karine Andreau; Delphine Poncet; Naoufal Zamzami; Jean-Luc Perfettini; Didier Métivier; David M. Ojcius; Marja Jäättelä; Guido Kroemer

A number of diseases are due to lysosomal destabilization, which results in damaging cell loss. To investigate the mechanisms of lysosomal cell death, we characterized the cytotoxic action of two widely used quinolone antibiotics: ciprofloxacin (CPX) or norfloxacin (NFX). CPX or NFX plus UV light (NFX*) induce lysosomal membrane permeabilization (LMP), as detected by the release of cathepsins from lysosomes. Inhibition of the lysosomal accumulation of CPX or NFX suppresses their capacity to induce LMP and to kill cells. CPX- or NFX-triggered LMP results in caspase-independent cell death, with hallmarks of apoptosis such as chromatin condensation and phosphatidylserine exposure on the plasma membrane. LMP triggers mitochondrial membrane permeabilization (MMP), as detected by the release of cytochrome c. Both CPX and NFX* cause Bax and Bak to adopt their apoptotic conformation and to insert into mitochondrial membranes. Bax−/− Bak−/− double knockout cells fail to undergo MMP and cell death in response to CPX- or NFX-induced LMP. The single knockout of Bax or Bak (but not Bid) or the transfection-enforced expression of mitochondrion-targeted (but not endoplasmic reticulum–targeted) Bcl-2 conferred protection against CPX (but not NFX*)-induced MMP and death. Altogether, our data indicate that mitochondria are indispensable for cell death initiated by lysosomal destabilization.

Collaboration


Dive into the Marja Jäättelä's collaboration.

Top Co-Authors

Avatar

Tuula Kallunki

University of California

View shared research outputs
Top Co-Authors

Avatar
Top Co-Authors

Avatar

Dorte Wissing

University of Düsseldorf

View shared research outputs
Top Co-Authors

Avatar

Lone Bastholm

University of Copenhagen

View shared research outputs
Top Co-Authors

Avatar

Ole Dines Olsen

University of Southern Denmark

View shared research outputs
Top Co-Authors

Avatar
Top Co-Authors

Avatar

Folmer Elling

University of Copenhagen

View shared research outputs
Top Co-Authors

Avatar
Top Co-Authors

Avatar
Researchain Logo
Decentralizing Knowledge