Baudino, Troy, A.

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Research:

Myc's Functions as a Transcription Factor

All of Myc’s effects rely on its functions as a transcription factor. Myc oncoproteins are members of the basic-helix-loop-helix-leucine zipper (b-HLH-Zip) family of transcription factors that bind to the canonical “E-box” sequences CACGTG or CATGTG. Myc's DNA binding and transactivation functions require its dimerization with Max (a small b-HLH-Zip protein). However, Max also associates with a dedicated group of b-HLH-Zip antagonists (Mad1, Mxi1, Mad 3, Mad4, Mnt and Mga) that have been thought to compete with Myc for Max, and which can also bind to E-box elements, but repress transcription.

MYC oncoproteins are overexpressed in approximately 70% of all human cancers and promote tumorigenesis by inducing signals that promote proliferation and angiogenesis. However, overexpression of Myc triggers apoptosis in normal cells, suggesting that Myc's apoptotic pathways must be disabled for Myc to promote tumor development. Indeed, it has been demonstrated that Myc activates the p53 apoptotic program through p19 ARF, a nucleolar tumor suppressor that inactivates p53's endogenous inhibitor Mdm2. Moreover, it has been shown that disruption of the Arf-p53-Mdm2 tumor suppressor pathway is a hallmark of Myc-driven lymphomas and may play roles in other types of cancer.

Role of Myc Oncoproteins in Development and Tumor Angiogenesis

The creation of conventional and conditional c-myc and N- myc knockout mice have established that Myc is required for cell cycle traverse of certain cell types, and for embryonic development, yet the exact reasons for lethality was previously unknown. By re-evaluating these knockout mice, our studies have demonstrated that c-Myc is required for vasculogenesis and angiogenesis during development, as well as during tumor progression. On the other hand, N-Myc appears to be required for primitive and definitive erythropoiesis. Using genetic approaches, and through the generation of GFP c- myc and N- myc knock-in/knockout mice, our current studies are to define the precise target cells and functions of N-Myc and c-Myc required for hematopoiesis and vasculogenesis.

Microarray and proteomic analyses have demonstrated that Myc provokes widespread changes in gene expression, yet the precise mechanism is still unresolved. It is possible that Myc can induce such a large response by acting as a regulator of cytokines that control cell growth and development. Our previous studies using c- myc knockout embryos and c- myc- deficient embryonic stem (ES) cells established that loss of c- myc is associated with coordinate and profound changes in the expression of various pro- and anti-angiogenic factors required for growth and modeling of the vasculature during development. Furthermore, teratoma studies with c- myc -/- ES cells demonstrated that Myc loss severely compromises tumorigenesis and that the small tumors that do develop (65%) lack any supporting vasculature.

Therefore, c-Myc appears to be the master angiogenic switch in cancer, which explains why activation of MYC oncogenes is such a highly selected event in cancer. Finally, our most recent experiments suggest a surprising mechanism by which Myc regulates the expression of many of these angiogenic cytokines by regulating factors that regulate the stability of the mRNAs. We are currently performing genetic and biochemical tests of this hypothesis.

Myc and its Role in the Cardiovascular System

Studies with targeted disruption of each of the myc loci have provided evidence in favor of differential function of their encoded proteins. c-myc knockout animals die at embryonic day 9.5 with abnormalities of the heart, pericardium, neural tube and a delay or failure in embryonic turning. N-myc knockout animals survive about 1 day longer than their c-myc knockout counterparts and show developmental defects in many of the tissues that normally express N-myc (mesonephros, gut, lung and central and peripheral nervous systems). These mice also display modest heart defects.

Although not expressed in the adult heart under normal physiological conditions, c-Myc is rapidly upregulated in response to hypertrophic stimuli. Indeed, along with c-fos and c-jun, c-myc is one of the first genes upregulated. It has been demonstrated that Myc is capable of sustaining hyperplastic growth in fetal cardiomyocytes. In addition, activation of Myc in adult myocardium produced changes in myocyte size, protein synthesis and cardiac-specific gene expression seen in cardiac hypertrophy. While the c-myc knockout mice display cardiac defects, it is not known whether these defects are secondary or primary to other defects observed in these animals. Therefore, our current studies are focusing on the effect of Myc loss specifically in the heart. In addition, we are examining the effects of Myc loss during pressure overload hypertrophy.

Recent Publications:

• Baudino, TA and Cleveland, JL. The Max Network Gone Mad.Mol Cell Biol 2001; 21(3):691-702.
• MacDonald PN, Baudino TA, Tokumaru H, Dowd DR, and Zhang C. Vitamin D receptor and nuclear receptor coactivators: crucial interactions in vitamin D-mediated transcription. Steroids 2001; 66(3-5):171-176.
• Zhang C, Baudino TA, Dowd DR, Tokumaru H, Wang W, and MacDonald PN. Ternary complexes and cooperative interplay between NCoA-62/Ski-interacting protein and steroid receptor coactivators in vitamin D receptor-mediated transcription. J Biol Chem 2001; 276:40614-40620.
• Baudino TA, McKay C, Pendeville-Samain H, Nilsson JA, Maclean KH, White EL, Davis AC, Ihle JN, and Cleveland JL. c-Myc is essential for vasculogenesis and angiogenesis during development and tumor progression. Genes Dev 2002; 16:2530-2543.

- Commentary in Nature Rev Cancer 2, 808, 2002.

• Baudino TA, Maclean KH, Brennan J, Parganas E, Yang C, Aslanian A, Lees JA, Sherr CJ, Roussel MF, and Cleveland JL. Myc-mediated proliferation and lymphomagenesis, but not apoptosis, are compromised by E2f1 loss. MolCell 2003; 4:905-914.

-Commentary in Cell Cycle 2:6, 496-499, 2003.

• Zindy F, Williams RT, Baudino TA, Rehg JE, Skapek SX, Cleveland JL, Roussel MF, and Sherr CJ. Arf tumor suppressor promoter monitors latent oncogenic signals in vivo. Proc Natl Acad Sci USA. 2003; 100 (26):15930-15935.
• Nilsson JA, Maclean KH , Keller UB, Pendeville H, Baudino TA, and Cleveland JL. Myc functions as a Mnt antagonist to induce proliferation, apoptosis and transformation. Mol Cell Biol 2004; 24:1560-1569.
• Davidoff AM, Ng CY, Zhang Y, Streck CJ, Mabry SJ, Barton SH, Baudino T, Zhou J, Kerbel RS, Vanin EF, and Nathwani AC. Careful Decoy Receptor Titering is Required to Inhibit Tumor Angiogenesis While Avoiding Adversely Altering VEGF Bioavailability. Mol Ther 2005; 11(2):300-310.
• Nilsson JA, Keller UB, Baudino TA, Yang C, Norton S, Brennan JA, Neale G, Porter CW, Kramer DL, and Cleveland JL. T argeting ornithine decarboxylase in Myc-induced lymphomagenesis prevents tumor formation. Cancer Cell2005 May; 7(5):433-44.
• Kasper LH, Boussaour F, Boyd K, Xu W, Biesen M, Rehg J, Baudino TA, Cleveland JL, and Brindle PK. Two transactivation mechanisms cooperate for the bulk of HIF-1-responsive gene expression. EMBO J, 2005 Oct 20, epub ahead of print.

Education:

• 1993 BS Biology Bradley University, Peoria, IL
• 1999 PhD Cell and molecular biology St. Louis University, St. Louis, MO
• Post-Doctoral Fellow, Biochemistry, St. Jude Children's Research Hospital, Memphis, TN

Contact Information:

Email: tbaudino@gw.med.sc.edu
Phone: 803-733-1562
Address: Building1 Room C-57
USC School of Medicine
Columbia, SC 29209