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Hsp70 protects against UVB induced apoptosis by preventing release of cathepsins and cytochrome c in human melanocytes
Linköping University, Department of Clinical and Experimental Medicine, Dermatology and Venerology . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Dermatology and Venerology . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Experimental Pathology . Linköping University, Faculty of Health Sciences.ORCID iD: 0000-0003-4075-159X
2007 (English)In: Carcinogenesis, ISSN 0143-3334, E-ISSN 1460-2180, Vol. 28, no 3, 537-544 p.Article in journal (Refereed) Published
Abstract [en]

Stress-induced heat shock protein 70 (Hsp70) effectively protects cells against apoptosis, although the anti-apoptotic mechanism is still undefined. Exposure of human melanocytes to heat and subsequent UVB irradiation increased the level of Hsp70 and pre-heating reduced UVB induced apoptosis. Immunofluorescence staining of Hsp70 in combination with staining of lysosomes (Lamp2) or mitochondria (Mitotracker®) in pre-heated UVB exposed cells showed co-localization of Hsp70 with both lysosomes and mitochondria in the surviving cell population. Furthermore, UVB induced apoptosis was accompanied by lysosomal and mitochondrial membrane permeabilization, detected as release of cathepsin D and cytochrome c, respectively, which were prevented by heat pre-treatment. In purified fractions of lysosomes and mitochondria, recombinant Hsp70 attached to both lysosomal and mitochondrial membranes. Moreover, in apoptotic cells Bax was translocated from a diffuse cytosolic location into punctate mitochondrial-like structures, which was inhibited by Hsp70 induction. Such inhibition of Bax translocation was abolished by transfection with Hsp70 siRNA. Furthermore, Hsp70 siRNA eliminated the apoptosis preventive effect observed after pre-heating. These findings show Hsp70 to rescue melanocytes from UVB induced apoptosis by preventing release of cathepsins from lysosomes, Bax translocation and cytochrome c release from mitochondria.

 

Abbreviations: AIF, apoptosis-inducing factor; Hsp, heat shock protein; NAG, ß-N-acetylglucosaminidase; tBid, truncated Bid; UV, ultraviolet

Place, publisher, year, edition, pages
2007. Vol. 28, no 3, 537-544 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-14401DOI: 10.1093/carcin/bgl152OAI: oai:DiVA.org:liu-14401DiVA: diva2:23439
Available from: 2007-05-14 Created: 2007-05-14 Last updated: 2017-12-13
In thesis
1. Regulation of UV induced apoptosis in human melanocytes
Open this publication in new window or tab >>Regulation of UV induced apoptosis in human melanocytes
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Malignant melanoma arises from the pigment producing melanocytes in epidermis and is the most aggressive type of skin cancer. The incidence of malignant melanoma is increasing faster than any other type of cancer in white population worldwide, with a doubling rate every 10-20 years. So far, the only identified external risk factor for malignant melanoma is UV exposure. Elimination of photodamaged cells by apoptosis (programmed cell death) is essential to prevent tumor formation. Melanocytes are considered relatively resistant to apoptosis, however, the regulation of apoptosis in melanocytes is still unknown.

The aim of this thesis was to investigate the apoptotic process following ultraviolet (UV) irradiation in primary cultures of human melanocytes. Focus was on regulation of mitochondrial stability by Bcl-2 family proteins and the possible participation of lysosomal proteases, cathepsins. UV irradiation activated the mitochondrial pathway of apoptosis, leading to cytochrome c release, caspase activation, and nuclear fragmentation. No change in protein expression of Bax and Bcl-2 was observed in response to UV. Instead, translocation of the Bcl-2 family proteins from cytosol to mitochondia was important in the regulation of survival and death of melanocytes. The findings further demonstrated permeabilization of the lysosomal membrane to occur early in the apoptotic process, resulting in cathepsin release into the cytosol. The cathepsins were potent pro-apoptotic mediators and triggered apoptosis upstream of Bax translocation and mitochondrial membrane permeabilization. In response to both heat and UV irradiation, there was a marked increase in expression of stress-induced heat shock protein 70 (Hsp70), which inhibited apoptosis by binding lysosomal and mitochondrial membranes and counteracting the release of cathepsins and cytochrome c. Furthermore, UV irradiation activated c-jun N-terminal kinase (JNK), which triggered apoptosis upstream of cathepsins release from the lysosomes. In addition, JNK mediated apoptosis through phosphorylation of pro-apoptotic Bim, which was released from anti-apoptotic Mcl-1, by UV induced Mcl-1 depletion.

This thesis illustrates that permeabilization of mitochondria and lysosomes and release of their constituents to the cytosol participates in UV induced apoptosis signaling in human melanocytes in vitro. The process is regulated by a complex network of pro- and anti-apoptotic proteins, exerting their effects through intracellular translocation and alteration of protein expression.

Place, publisher, year, edition, pages
Institutionen för biomedicin och kirurgi, 2007
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 997
Keyword
apoptosis, UV, melanocyte, lysosome, cathepsin, Bcl-2, Bax, Hsp70, JNK
National Category
Dermatology and Venereal Diseases
Identifiers
urn:nbn:se:liu:diva-8749 (URN)978-91-85831-97-5 (ISBN)
Public defence
2007-05-25, Berzeliussalen, Campus US, Linköpings Universitet, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2007-05-14 Created: 2007-05-14 Last updated: 2017-08-30

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Bivik, CeciliaRosdahl, IngerÖllinger, Karin

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