Student Theses and Dissertations

Date of Award

2002

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Heintz Laboratory

Abstract

Zipro 1 a zinc finger transcnption factor that has a restricted pattern of expression in several tissues. The main cells expressing Ziprol 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 Ziprol is involved in proliferation GCs, Hair follicles and the Cranio-facial process. Overexpression of Ziprol results an increase in the number of G C s , this increase in G C s 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. Ziprol null mutants show a restricted phenotype of decreases in proliferation in the cranio-facial process. To understand h o w Ziprol effects these changes it is necessary to know which genes Ziprol regulates. Using gene arrays we have found a gene, which is regulated by Ziprol this gene, is the Ski oncogene. The regulation can be seen in the Ziprol"'~, which show deficits in Ski expression in the cranio-facial process. This coupled with database searches of genomic sequences using the consensus Ziprol 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 Ziprol. Also transcription from this promotor under the control of Ziprol is highly context dependant In M C F 7 (human breast cancer) under in Fetal Calf serum the Ski promoter is activated, in N I H 3T3 cells the Ski promoter cannot be activated by Ziprol. Deletion of the 2 Z B S abolishes transcnption. The reason for the specificity has been shown to be the presence of SDF-lalpha in the Fetal Bovine Media this serum factor is downregulated in adulthood. SDF-lalpha modulates Ziprol activity through a phosphorylation dependant modulation of SUMOlaytion . This study has shown a role for Ziprol 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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