Student Theses and Dissertations

Date of Award

2002

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Thesis Advisor

Nathaniel Heintz

Keywords

Zipro1, zinc finger transcription factor, cerebellar granule cells, Ski oncogene, cell proliferation, SDF-1α

Abstract

Zipro 1 a zinc finger transcription factor that has a restricted pattern of expression in several tissues. The main cells expressing Zipro1 are proliferating cells from epidermal lineages. This includes the cerebellar granule cells (GCs), nasal epithelia and dermal papilla. Through gene dosage experiments we have shown that Zipro1 is involved in proliferation GCs, Hair follicles and the Cranio-facial process. Overexpression of Zipro1 results an increase in the number of GCs, this increase in GCs directly regulates the appearance of secondary fissure in the cerebellum. Overexpression also results in follicular dysplasia caused by an increase in cells within dermal papilla. Zipro1 null mutants show a restricted phenotype of decreases in proliferation in the cranio-facial process. To understand how Zipro1 effects these changes it is necessary to know which genes Zipro1 regulates. Using gene arrays we have found a gene, which is regulated by Zipro1 this gene, is the Ski oncogene. The regulation can be seen in the Zipro1-/-, which show deficits in Ski expression in the cranio-facial process. This coupled with database searches of genomic sequences using the consensus Zipro1 binding site (ZBS) has shown us Ski promotor region contains 2 such sites. Using a transciption assay utilizing a Secreated Alkaline Phosphotase (pSEAP sytem from Clontech) it was shown that transciption from the Ski promotor is dependant on the presence of Zipro1. Also transcription from this promotor under the control of Zipro1 is highly context dependant In MCF7 (human breast cancer) under in Fetal Calf serum the Ski promoter is activated, in NIH 3T3 cells the Ski promoter cannot be activated by Zipro1. Deletion of the 2 ZBS abolishes transcnption. The reason for the specificity has been shown to be the presence of SDF-1alpha in the Fetal Bovine Media this serum factor is downregulated in adulthood. SDF-1alpha modulates Zipro1 activity through a phosphorylation dependant modulation of SUMOlaytion . This study has shown a role for Zipro1 acts as a rheostat that is available to adjust the numbers of cells in highly proliferative populations.

Comments

A thesis presented to the faculty of The Rockefeller University in partial fulfillment of the requirements for the degree of Doctor of Philosophy

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