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JNK mediates UVB-induced apoptosis upstream lysosomal membrane permeabilization and Bcl-2 family proteins
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Dermatologi och venerologi. Linköpings universitet, Hälsouniversitetet.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Experimentell patologi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Laboratoriemedicinskt centrum, Klinisk patologi och klinisk genetik.ORCID-id: 0000-0003-4075-159X
2008 (Engelska)Ingår i: Apoptosis (London), ISSN 1360-8185, E-ISSN 1573-675X, Vol. 13, nr 9, s. 1111-1120Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

UVB irradiation induced phosphorylation of JNK and subsequent apoptosis in human melanocytes. Depletion of both JNK1 and JNK2 expression using siRNA transfection, protected against apoptosis, as detected by decreased nuclear fragmentation and caspase-3 activity, as well as reduced translocation of Bax to mitochondria. Moreover, release of cathepsin B and D from lysosomes to the cytosol was reduced when JNK expression was suppressed by siRNA, demonstrating a JNK dependent regulation of lysosomal membrane permeabilization. In unirradiated control melanocytes, coimmunoprecipitation showed that Bim was sequestered by Mcl-1, which had a pro-survival function. After UVB irradiation, a significant decrease in Mcl-1 protein level was found, which was prevented by addition of a proteasome inhibitor. The interaction between Bim and Mcl-1 was reduced in response to UVB irradiation and Bim was phosphorylated in a JNK dependent manner. In conclusion, these findings Suggest JNK to have an important pro-apoptotic function following UVB irradiation in human melanocytes, by acting upstream of lysosomal membrane permeabilization and Bim phosphorylation.

Ort, förlag, år, upplaga, sidor
2008. Vol. 13, nr 9, s. 1111-1120
Nyckelord [en]
UV, Cathepsin, JNK, Mcl-1, Bim
Nationell ämneskategori
Medicin och hälsovetenskap
Identifikatorer
URN: urn:nbn:se:liu:diva-16886DOI: 10.1007/s10495-008-0240-7OAI: oai:DiVA.org:liu-16886DiVA, id: diva2:174433
Anmärkning
The original publication is available at www.springerlink.com: Cecilia Bivik and Karin Öllinger, JNK mediates UVB-induced apoptosis upstream lysosomal membrane permeabilization and Bcl-2 family proteins, 2008, Apoptosis (London), (13), 9, 1111-1120. http://dx.doi.org/10.1007/s10495-008-0240-7 Copyright: Springer Science Business Media http://www.springerlink.com/ Tillgänglig från: 2009-04-29 Skapad: 2009-02-20 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
Ingår i avhandling
1. Regulation of UV induced apoptosis in human melanocytes
Öppna denna publikation i ny flik eller fönster >>Regulation of UV induced apoptosis in human melanocytes
2007 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Institutionen för biomedicin och kirurgi, 2007
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 997
Nyckelord
apoptosis, UV, melanocyte, lysosome, cathepsin, Bcl-2, Bax, Hsp70, JNK
Nationell ämneskategori
Dermatologi och venereologi
Identifikatorer
urn:nbn:se:liu:diva-8749 (URN)978-91-85831-97-5 (ISBN)
Disputation
2007-05-25, Berzeliussalen, Campus US, Linköpings Universitet, Linköping, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2007-05-14 Skapad: 2007-05-14 Senast uppdaterad: 2020-03-29

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Bivik, CeciliaÖllinger, Karin

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