Localisation of Protein Kinase C in Apoptosis and Neurite Outgrowth

Abstract

Protein kinase C (PKC) is a family of serine/threonine kinases, which are subgrouped into classical (a, bI, bII, g), novel (d, e, h, q) and atypical (z, i/l) isoforms. One major aim of this thesis work was to investigate if altered levels of PKC isoforms influence the apoptotic responses of malignant cell-lines. We show that overexpression of PKCd or PKCq renders SK-N-BE(2) neuroblastoma cells sensitive to apoptosis induced by phorbol esters or C2-ceramide. Moreover, overexpression of PKCa, PKCd or PKCe sensitises both androgen-dependent and androgen-independent prostate cancer cells to phorbol ester-induced cell-death. The apoptotic effects of PKCd and PKCq in neuroblastoma cells are independent on the catalytic activity of the enzymes and the isolated regulatory domain (RD) of PKCq induces apoptosis in neuroblastoma cells. Induction of apoptosis depends on the localisation of PKCqRD to the Golgi complex, which is mediated by the C1b domain of the protein. Mutation of a single amino acid residue, Met-267 in PKCqC1b, blocks both the Golgi localisation and the apoptotic effect of the PKCqRD.



Previous studies have shown that PKCe induces neurites in neuroblastoma cells. Here we report that treatment with cell-permeable C2-ceramide inhibits PKCe-induced neurite formation, conceivably by relocating the protein from the cytosol to the perinuclear region. Mutation of Asp-257 and Met-278 (the latter corresponding to Met-267 in PKCq) in PKCe blocks the C2-ceramide induced translocation of PKCe. Furthermore, the mutated variant of PKCe still induces neurites after C2-ceramide treatment. Thus, the specific subcellular localisation of PKCq and PKCe are important for their biological activities.

• author: Schultz, Anna
• supervisor: Christer Larsson
• opponent: PhD Iglesias, Teresa, Universidad Autonóma de Madrid, Spain
• organization: Department of Translational Medicine
• publishing date: 2005
• type: Thesis
• publication status: published
• subject: Cancer and Oncology
• keywords: onkologi, cancer, Medicine (human and vertebrates), Medicin (människa och djur), Cytology, oncology, cancerology, Cytologi, Prostate Cancer, Neuroblastoma, Ceramide, Golgi Apparatus, Neurite outgrowth, Apoptosis, Protein Kinase C, C1 domain
• pages: 104 pages
• defense location: Main Lecture Hall, Pathology Building, University Hospital MAS, Malmö
• defense date: 2005-05-20 09:15:00
• ISBN: 91-85439-36-3
• language: English
• LU publication?: yes
• additional info: Anna Schultz, Jan-Ingvar Jönsson and Christer Larsson. 2003. The regulatory domain of protein kinase C-? localises to the Golgi complex and induces apoptosis in neuroblastoma and Jurkat cells. Cell Death. Differ., vol 10 pp 662-675.; Anna Schultz and Christer Larsson. 2004. Ceramide infl uences neurite outgrowth and neuroblastoma cell apoptosis regulated by novel protein kinase C isoforms. J. Neurochem., vol 89 pp 1427-1435.; Anna Schultz, Mia Ling and Christer Larsson. 2004. Identification of an amino acid residue in the protein kinase C C1b domain crucial for its localization to the Golgi network. J. Biol. Chem., vol 279 pp 31750-31760.; Anna Schultz and Christer Larsson. . Protein kinase C-? induces cell death both inandrogen-dependent and androgen-independent prostate cancer cells. (manuscript) The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Molecular Medicine (013031200)
• id: 506dddcb-501b-479e-b024-730dc0b717b3 (old id 544847)
• date added to LUP: 2016-04-01 15:23:45
• date last changed: 2018-11-21 20:34:13