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Cloning and characterisation of an osteoblast-specific transcription factor that functionally synetgize with fos/jun to regulate expression of collagenase by parathyroid hormone

Objective



Collagenase belongs to the Metalloproteinase family of proteins, that a involved in degradation of extracellular matrix (ECM) components. Collagens are the major components of cartilage and bone ECM. High level of collagenase expression has been detected in osteoblast cells (that are bone precursors) and has been associated with bone formation in mouse development. Thight balance of synthesis and degradation of the ECM is essential for the normal development of an organism. An aberant activity of MMPs has been found to be involved in a variety of pathological processes.
In tissue culture cells, collagenase expression is controlled by a broa spectrum of extracellular stimuli. Among them, the oncoprotein complex AP1 is required but not sufficient to mediate inducibility by parathyroid hormone (PTH). Collagenase promoter is known to contain an AP1 regulatory element (TRE), and recently sequence comparisons with the osteocalcine promoter has revealed the presence of an osteoblast specific element (OSE) that has been shown to cooprerate with TRE in the activation of collagenase by PTH in a tissue specific manner.
To our knowledge, no osteoblast-specific transcription factor has yet been identified. Therefore our aims are (1) to identify and isolate the osteoblast-specific factor (OSF) binding to the collagenase promoter, (2) to biochemically characterise the protein and to determine its functional domains (DNA binding domain; transactivation domain), (3) to analyse possible regulatory mechanisms to modulate DNA binding and
transactivation, and (4) to determine the mechanisms of functional cooperativity between OSF and Fos/Jun binding to the collagenase promoter. Training content (objective, benefit and expected impact)
The cloning of a specific member of the family of runt proteins from osteoblastic cells will be the first example of a transcription factor that mediates cell type-specific expression in cells of the osteoblastic lineage. Comparing the properties of the newly isolated factor with known members of the family (that were isolated from lymphoid cells) may help to understand mechanisms of cell type-specific gene expression. Elucidation of the mechanisms of functional synergism between AP-1 and OSF may also explain the principles of tissue-specific expression of collagenase in bone and in fos-induced osteosarcoma. In light of the function of the Drosophila runt protein to be involved in body segmentation, in addition to regulation of collagenase, OSF may even serve as a critical regulator of cartilage/bone-specific differentiation programs.

Funding Scheme

RGI - Research grants (individual fellowships)

Coordinator

Stiftung Deutsches Krebsforschungszentrum
Address
280,Im Neuenheimer Feld
69120 Heidelberg
Germany

Participants (1)

Not available
France