The role of the ubiquitin proteasome system in cerebellar development and medulloblastoma.

07:00 EST 1st January 2000 | BioPortfolio

Summary of "The role of the ubiquitin proteasome system in cerebellar development and medulloblastoma."

Cerebellar granule cells precursors are derived from the upper rhombic lip and migrate tangentially independent of glia along the subpial stream pathway to form the external germinal zone. Postnatally, granule cells migrate from the external germinal zone radially through the Purkinje cell layer, guided by Bergmann glia fibers, to the internal granular cell layer.Medulloblastomas (MBs) are the most common malignant childhood brain tumor. Many of these tumors develop from precursor cells of the embryonic rhombic lips. Four main groups of MB are recognized. The WNT group of MBs arise primarily from the lower rhombic lip and embryonic brainstem. The SHH group of MBs originate from cerebellar granule cell precursors in the external germinal zone of the embryonic cerebellum. The cellular origins of type 3 and type 4 MBs are not clear.Several ubiquitin ligases are revealed to be significant factors in development of the cerebellum as well as in the initiation and maintenance of MBs. Proteasome dysfunction at a critical stage of development may be a major factor in determining whether progenitor cells which are destined to become granule cells differentiate normally or become MB cells. We propose the hypothesis that proteasomal activity is essential to regulate the critical transition between proliferating granule cells and differentiated granule cells and that proteasome dysfunction may lead to MB. Proteasome dysfunction could also account for various mutations in MBs resulting from deficiencies in DNA checkpoint and repair mechanisms prior to development of MBs.Data showing a role for the ubiquitin ligases β-TrCP, FBW7, Huwe1, and SKP2 in MBs suggest the possibility of a classification of MBs based on the expression (over expression or under expression) of specific ubiquitin ligases which function as oncogenes, tumor suppressors or cell cycle regulators.


Journal Details

This article was published in the following journal.

Name: Molecular brain
ISSN: 1756-6606
Pages: 64


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Medical and Biotech [MESH] Definitions

Complexes of enzymes that catalyze the covalent attachment of UBIQUITIN to other proteins by forming a peptide bond between the C-terminal GLYCINE of UBIQUITIN and the alpha-amino groups of LYSINE residues in the protein. The complexes play an important role in mediating the selective-degradation of short-lived and abnormal proteins. The complex of enzymes can be broken down into three components that involve activation of ubiquitin (UBIQUITIN-ACTIVATING ENZYMES), conjugation of ubiquitin to the ligase complex (UBIQUITIN-CONJUGATING ENZYMES), and ligation of ubiquitin to the substrate protein (UBIQUITIN-PROTEIN LIGASES).

A malignant neoplasm that may be classified either as a glioma or as a primitive neuroectodermal tumor of childhood (see NEUROECTODERMAL TUMOR, PRIMITIVE). The tumor occurs most frequently in the first decade of life with the most typical location being the cerebellar vermis. Histologic features include a high degree of cellularity, frequent mitotic figures, and a tendency for the cells to organize into sheets or form rosettes. Medulloblastoma have a high propensity to spread throughout the craniospinal intradural axis. (From DeVita et al., Cancer: Principles and Practice of Oncology, 5th ed, pp2060-1)

The act of ligating UBIQUITINS to PROTEINS to form ubiquitin-protein ligase complexes to label proteins for transport to the PROTEASOME ENDOPEPTIDASE COMPLEX where proteolysis occurs.

A single protein comprised of tandem repeats of the UBIQUITIN 78-amino acid sequence. It is a product of the polyubiquitin gene which contains multiple copies of the ubiquitin coding sequence. Proteolytic processing of ubiquitin C results in the formation of individual ubiquitin molecules. This protein is distinct from POLYUBIQUITIN, which is a protein formed through isopeptide linkage of multiple ubiquitin species.

A class of enzymes that catalyzes the ATP-dependent formation of a thioester bond between itself and UBIQUITIN. It then transfers the activated ubiquitin to one of the UBIQUITIN-PROTEIN LIGASES.

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