REGULATED UPTAKE OF BIOPOLYMERS Role of cell surface proteoglycans Implications for drug and gene delivery

Abstract

Cells continuously export, import, and recycle molecules over the plasma membrane. Internalization, i.e. cellular import of extracellular material, is a fundamental process, which provides cells with nutrients and enables the immune cells of higher organisms to remove debris, sample their surroundings for antigens and to fight microbes. Moreover, internalization regulates complex cellular signalling events involved in cellular division, motion, and communication with the surrounding extracellular matrix. However, the preserved routes of internalization are exploited by a large number of microbes and pathological factors such as bacterial toxins and viral proteins. The HIV-1 TAT protein was shown to enter cells and to target their nuclei, thus acting as a paracrine transcription factor, a finding that initiated the field of so called cell penetrating peptides (CPPs). Due to their ability to efficiently deliver macromolecular cargo over the plasma membrane, CPPs have proven to be useful tools in basic research. More importantly, the technology has been shown to enhance delivery of a number of macromolecular compounds in vivo, including anticancer drugs.



The proteoglycan family of molecules has previously been shown to participate in the interaction with and internalization of a number of ligands, including polyamines, growth factors, morphogens, and microbes. This thesis deals with the role of proteoglycans in cellular internalization of charged biopolymers, i.e. the polyamine family of growth factors, HIV-Tat peptide, antimicrobial peptides, and nucleic acids. The presented findings bring proteoglycans into focus as a general internalization pathway for charged macromolecules, with implications for drug and gene delivery.

• author: Sandgren, Staffan
• supervisor: Mattias Belting
• opponent: professor Lebleu, Bernard, Laboratoire des Défenses Antivirales et Antitumorales, Université Montpellier II, Montpellier, Franc
• organization: Breastcancer-genetics
• publishing date: 2005
• type: Thesis
• publication status: published
• subject: Cancer and Oncology
• keywords: Medicin (människa och djur), Cytology, oncology, proliferation, differentiation, Medicine (human and vertebrates), growth factor, cancer, drug delivery, gene therapy, LL-37, HIV-Tat, cell penetrating peptides, polyamines, heparan sulfate, onkologi, Cytologi, cancerology, internalization, proteoglycans
• pages: 143 pages
• defense location: GK-salen BMC Sölvegatan 19 Lund
• defense date: 2005-10-14 09:00:00
• ISBN: 91-85439-77-0
• language: English
• LU publication?: yes
• additional info: S Sandgren and M Belting. 2003. Suramin selectively inhibits carcinoma cell growth that is dependent on extracellular polyamines. Anticancer Res, vol 23 pp 1223-8.; K Mani, S Sandgren, E Weber, F Cheng, L-Å Fransson and M Belting. . Common internalization mechanism for HIV-Tat protein transduction domain and polyamines in human carcinoma cells: Implications for tumor growth inhibition. (manuscript); S Sandgren, F Cheng and M Belting. 2002. Nuclear targeting of macromolecular polyanions by an HIV-Tat derived peptide. Role for cellsurface proteoglycans. J Biol Chem, vol 227 pp 38877-83.; S Sandgren, A Wittrup, F Cheng, M Jönsson, E Eklund, S Busch and M Belting. 2004. The human antimicrobial peptide LL-37 transfers extracellular DNA plasmid to the nuclear compartment of mammalian cells via lipid rafts and proteoglycan-dependent endocytosis. J Biol Chem, vol 279 pp 17951-6.; S Sandgren, A Wittrup, J Lilja, M Mörgelin and M Belting. . Secreted components induce DNA internalization in mammalian cells. (manuscript)
• id: 9f24a326-81b1-4c5a-acbc-ee8080a39c1c (old id 545423)
• date added to LUP: 2016-04-01 16:31:43
• date last changed: 2018-11-21 20:42:07