DOI

https://doi.org/10.25772/EPF4-6V67

Defense Date

1993

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Microbiology & Immunology

First Advisor

Eric H. Westin

Abstract

The human cellular proto-oncogene c-myb has been implicated as important in the regulation of hematopoietic cell growth and differentiation. Aberrant expression of this gene and chromosomal aberrations near the c-myb locus have been associated with a number of carcinogenic processes. An alternatively spliced CDNA clone of c-myb, pMbm-2, contains unique 5’ sequences which replace exon 1. The existence of this 5’ divergent CDNA clone led us into a study of the promoter activity of the c-myb gene.

Intron 1 of c-myb is highly conserved between human and mouse throughout the intron, while only those sequences directly adjacent to exons 1 and 2 are conserved between human and chicken. The unique sequence of pMbm-2 was located directly adjacent to exon 2, suggesting that it arose as a product of alternative transcription initiation within intron 1. A cluster of transcription start sites was detected at the 5’ end of exon 2. Levels of messages utilizing these start sites are expressed proportionally to those arising from the primary promoter. Functional characterization of this region revealed that this region can function as a promoter. Deletion studies have revealed the presence of negative and positive regulatory elements within this region which are utilized with different efficiencies in different cell lines. These studies suggest that cis or trans factors acting in this region may serve a dual function in both attenuation and transcription initiation.

Studies of the c-myb promoter utilizing the acute lymphoblastic cell line CCRF-CEM revealed that a portion of the c-myb promoter is lost in this cell line. The rearranged locus, which we have designated MRR (myb rearranged region), has been Cloned and mapped to chromosome 6. The MR sequence is linked to the c-myb locus, suggesting that the rearrangement is due to a submicroscopic deletion. The rearrangement appears to have no effect on c-myb promoter activity as analyzed in CCRF-CEM cells. The normal locus of the MRR sequence shows a high degree of homology to a member of the myc family of oncogenes. Therefore, although attenuation may be the primary mechanism of c-myb regulation, the existence of a second promoter in the c-myb gene and a rearrangement of the primary c-myb promoter in a leukemia cell line suggests that other regions at the 5’ end of this gene are important in the regulation of c-myb transcription.

Comments

Scanned, with permission from the author, from the original print version, which resides in University Archives.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

6-29-2017

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