Molekulare Mechanismen der Regulation von Matrixkontakten und Migration melanozytärer Zellen durch das Protein MIA

In Germany malignant tumors are the second most frequent cause of death following diseases of the circulatory system. Malignant melanoma is a type of skin cancer, which has mainly developed in the Caucasian population. During the last 10 years an increase has been observed, probably associated with a change in behavior during leisure time especially frequent sunbathing. The protein MIA (Melanoma Inhibitory Activity) plays an important role within the scope of cell attachment and tissue invasion of malignant melanoma. This thesis refers to the MIA protein: Its interaction partners, its influence on regulation of cellular signaling pathways and on the MIA-expression regulatory pathways. All melanoma cell lines show a strong expression of MIA protein. MIA interacts with proteins of the extracellular matrix (ECM), specifically with fibronectin and laminin. Subsequently it masks the binding sites for the integrins. The cells detach from the ECM and in vitro migration is observed, in vivo metastasis occurs. In contrast melanocytes, fibroblasts and keratinocytes do not express MIA. This leads to the conclusion that cellular signalling pathways are activated during the progression of melanoma. The expression of MIA may be induced via these pathways. They were investigated using the method of in vivo expression cloning. A voluminous library of dodecamer-peptid-sequences was screened using the phage display method to identify interaction partners of MIA other than known ECM proteins. In order to verify that MIA interacts with certain domains of fibronectin and laminin, the peptides found were checked for consensus sequences with the protein sequences of fibronectin and laminin. The constitutive activation of NFkB is a unique feature of several kinds of tumors including breast cancer, colon cancer, pancreatic cancer, ovarian cancer and melanoma. Integrins are involved in the regulation of survival of cells via regulation of NFkB activity.Therefore the influence of MIA on the regulation of NFkB was examinated. The classical AP-1 protein is composed of Fos and Jun, which are the products of the c-Fos and c-Jun genes. c-Jun and also AP-1 are end-points of numerous different intracellular signalling pathways. Therefore the influence of MIA on the regulation of AP-1 protein was investigated. Phosphorylation and dephosphorylation play key roles in regulatory processes in cells. The regulation of protein tyrosine kinases (PTKs) by MIA was investigated with a non-radioactive protein tyrosine kinase assay. The protein tyrosine phosphatases (PTPs) are the counterparts of the PTKs. Using a similar assay the regulation of PTPs by MIA was measured. The influence of MIA on the activity of MAP kinases was investigated using a specific MAP kinase assay. This work provides a additional insight into the molecular function of the protein MIA especially on its role in the regulation of attachment and motility of melanoma cells.

Grantor dc:publisher

Publikationsserver der RWTH Aachen University

Year dc:date

2003

Author dc:creator

• Breibach, Ines

Contributors dc:contributor

• Büttner, Reinhard

• info:eu-repo/classification/ddc/610
• Medizin
• melanoma
• melanoma inhibitory activity
• cellular signalling pathways

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

ger

Identifier

https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-120611%22

OAI identifier oai:identifier

oai:publications.rwth-aachen.de:58776