Susanna M. Mac
| Years in MSTP | 1993-2001 |
| PhD | Oncology, 1999 |
| Mentor | Peggy J. Farnham |
| Thesis |
Myc Target Genes in Neoplasia |
| Fellowship | Salk Institute, La Jolla, California |
| Current Position |
Senior manager, medical writing, Amgen Pharmaceuticals |
Thesis Abstract
Although the Myc family of transcription factors is upregulated in many human tumors, it is unclear which genes are targets for the deregulated Myc. Previous studies suggest that hamster and rat carbamoyl phosphate synthase, aspartate transcarbamylase, dihydroorotase (cad) genes are regulated by c-Myc.
Of all the putative c-Myc target genes, only cad showed loss of cell cycle dependent regulation in rat cells nullizygous for c-myc. However, it was unknown whether upregulation of CAD, which performs the first three rate-limiting steps of pyrimidine biosynthesis, contributes to c-Myc's role in human neoplasia.
I have cloned and characterized the human cad promoter to explore this possibility. c-Myc can bind to an E box in this promoter, and cell cycle dependent regulation of transcription is dependent upon this same E box. However, the increased amounts of c-Myc found in Burkitt's lymphoma do not lead to increased cad mRNA.
Although c-Myc is important for the normal transcriptional control of the cad gene, it is unlikely that increased CAD levels mediate c-Myc-induced neoplasia. Therefore, an understanding of how c-Myc contributes to neoplasia requires the identification of additional Myc target genes.
To better understand the Myc family, I have identified genes regulated by N-Myc. N-myc is amplified in some cases of neuroblastoma and serves as a prognostic factor for this disease. Results of a differential expression screen yielded several possible N-Myc target genes. After measuring expression of these genes in primary neuroblastomas, I found that only rcc1/chc1 was upregulated in primary tumors having amplified N-myc.
Rcc1/Chc1 plays a role in both chromosome condensation and traversal of the G1/S phase boundary. Therefore, my studies suggest that Rcc1/Chc1 may be an effector of N-Myc mediated neoplasia.
Publications
Mac SM, Farnham PJ. 2000. CAD, a c-Myc target gene, is not deregulated in Burkitt's lymphoma cell lines. Mol Carcinog 27:84-96.
Mac SM, D'Cunha CA, Farnham PJ. 2000. Direct recruitment of N-myc to target gene promoters. Mol Carcinog 29:76-86.