Scott Blume, MD


Rank:
Associate Professor

Division: Hematology & Oncology

Campus Address: BBRB 765

Phone: (205) 975-2409

Email: scottblume@uabmc.edu



Departmental Affiliation(s):
Primary: Medicine

Secondary: Biochemistry and Molecular Genetics

Interdisciplinary Genetics Graduate Program

Comprehensive Cancer Center (Cancer Cell Biology and Drug Discovery Programs)

Biosketch:
Scott Blume received his bachelor's degree in Biochemistry from the University of Alabama in 1982. His undergraduate research dealt with the kinetics of tryptophan synthetase and was performed under the direction of Dr. John K. Hardman. He received his doctorate degree from the University of Alabama in 1986, and performed post-doctoral research on DNA-binding drugs and gene amplification from 1987-91 under the direction of Dr. Donald M. Miller. He is an Associate Scientist in the Comprehensive Cancer Center, and a member of the faculty of the Graduate School. His research has been funded by the American Cancer Society, the Department of Defense Breast Cancer Research Program, the National Heart, Lung, and Blood Institute, and the National Cancer Institute.

Society Memberships:
American Association for Cancer Research

Research Description:
Specific regulation of gene expression at the translational level – through sequence-specific RNA-binding proteins and complex 5′-untranslated RNA sequences; dysregulation of gene-specific translational control mechanisms in cancer.
Translation initiation is generally accomplished via ribosomal scanning from the beginning (5′-end) of the mRNA, and for many genes this a relatively efficient process which is not subject to specific regulatory controls. However, the genes most critical to the control of cellular proliferation and survival (e.g. protooncogenes, growth factor receptors, and apoptotic regulators) are associated with very long, highly structured 5′-untranslated leader sequences which present significant obstacles to 40S ribosomal scanning and translation initiation. These complex 5′-UTRs serve essentially as "RNA promoters", with structural features and regulatory protein binding sites which provide the opportunity for specific regulation of gene expression at the translational level. Such features include upstream open reading frames (uORFs), which derail the scanning ribosome, and internal ribosomal entry sites (IRESs), which recruit the 40S ribosomal subunit into the vicinity of the authentic translation initiation codon. Importantly, these do not appear to be static structural features, rather they are regulated through dynamic interactions with sequence-specific RNA-binding proteins. Roughly 8% of all human genes encode RNA-binding proteins, yet we are just beginning to profile the spectrum of RNA-binding proteins and their functions in regulating gene expression. In fact, we are just now beginning to realize that these RNA-binding translation-regulatory proteins are capable of a degree of sequence specificity rivaling that of the much more thoroughly studied DNA-binding transcription factors, whose roles in gene expression and in tumorigenesis have been well-established over the past 20 years. Our research has focused on two genes, the protooncogene c-myc and the potent anti-apoptotic factor IGF1R, both of which are directly implicated in human breast cancer pathogenesis, and both of which are regulated at the translational level. In particular, we are investigating the IGF1R IRES, the c-myc uORF, and the RNA-binding proteins interacting with each of these complex 5′-untranslated sequences. We hypothesized that the dynamic, competitive interactions between these RNA-binding proteins and the IGF1R and c-myc 5′-UTRs may determine the functional state of the mRNA (whether it is actively translated, temporarily repressed, or permanently sequestered to facilitate the induction of apoptosis; molecular triage), and have accumulated data which support this hypothesis. Perhaps most importantly, our data indicate that pathological alterations in the activities of these RNA-binding translation-regulatory proteins may be responsible for dysregulation of gene expression in human breast cancer cells, and may contribute significantly to the molecular pathogenesis of this disease. Ultimately, this work is intended to establish gene-specific translational control mechanisms as targets for development of molecular therapeutic interventions.


PostDoc Positions Available:
One NIH-funded postdoctoral position is available in the laboratory of Dr. Scott Blume to study RNA-binding proteins and dysregulated translational control mechanisms in breast tumor cells. Ph.D. or equivalent degree is required. Send curriculum vitae and names of three references to: Dr. Scott Blume, 508 Wallace Tumor Institute, 1720 2nd Ave. S, Birmingham, AL 35294-3300.


Selected Publications:
•Meng, Z., Jackson, N.L., Shcherbakov, O.D., Choi, H., & Blume, S.W. (2010) The human IGF1R IRES likely operates through a Shine-Dalgarno-like interaction with the G961 loop (E-site) of the 18S rRNA and is kinetically modulated by a naturally-polymorphic polyU loop. J. Cell. Biochem. (in press).
•Blume, S.W., Jackson, N.L., Frost, A.R., Grizzle, W.E., Shcherbakov, O.D, Choi, H., Meng, Z. (2010) Northwestern profiling of potential translation-regulatory proteins in human breast epithelial cells and malignant breast tissues: evidence for pathological activation of the IGF1R IRES. Exp. Mol. Pathol. (in press).
•Choi, H., Jackson, N.L., Shaw, D.R., Emanuel, P.D., Liu, Y. L., Tousson, A., Meng, Z., & Blume, S.W. (2008). mrtl – A translation / localization regulatory protein encoded within the human c-myc locus and distributed throughout the endoplasmic and nucleoplasmic reticular network. J. Cell. Biochem. 105: 1092-1108. GenBank Accession BK006467 and DAA06340.
•Meng, Z., Jackson, N.L., Choi, H., King, P.H., Emanuel, P.D., & Blume, S.W. (2008) Alterations in RNA-binding activities of IRES-regulatory proteins as a mechanism for physiological variability and pathological dysregulation of IGF-IR translational control in human breast tumor cells. J. Cell Physiol. 217: 172-83.
•Meng, Z., King, P.H., Nabors, L.B., Jackson, N.L., Chen, C-Y., Emanuel, P.D., & Blume, S.W. (2005) The ELAV RNA-stability factor HuR binds the 5'-untranslated region of the human IGF1R transcript and differentially represses cap-dependent and IRES-mediated translation. Nucleic Acids Res. 33: 2962-2979.
•Blume, S.W., Miller, D.M., Guarcello, V., Shrestha, K., Meng, Z., Snyder, R.C., Grizzle, W.E., Ruppert, J.M., Gartland, G.L., Stockard, C.R., Jones, D.E., & Emanuel, P.D. (2003) Inhibition of tumorigenicity by the 5'-untranslated RNA of the human c-myc P0 transcript. Exp. Cell Res. 288: 131-142.
•Meng, Z., Snyder, R.C., Shrestha, K., Miller, D.M., Emanuel, P.D., & Blume, S.W. (2003) Evidence for Differential Ribonucleoprotein Complex Assembly In Vitro on the 5′-Untranslated Region of the Human IGF-IR Transcript. Mol. Cell. Endocrinol. 200: 127-140.
•Blume, S.W., Meng, Z., Shrestha, K., Snyder, R.C., & Emanuel, P.D. (2003) The 5′-untranslated RNA of the human dhfr minor transcript alters transcription pre-initiation complex assembly at the major (core) promoter. J. Cell. Biochem. 88: 165-180.
•Kar, S.R., Lebowitz, J., Blume, S., Taylor, K.B., & Hall, L.M. (2001) SmtB-DNA and protein-protein interactions in the formation of the Cyanobacterial Metallothionein repression complex: Zn2+ does not dissociate the protein-DNA complex in vitro. Biochemistry 40:
•Blume, S.W., Lebowitz, J., Zacharias, W., Guarcello, V., Mayfield, C.A., Ebbinghaus, S.W., Bates, P., Jones, D.E. Jr., Trent, J., Vigneswaran, N., & Miller, D.M. (1999) The integral divalent cation within the intermolecular purine*purine.pyrimidine structure: A variable determinant of the potential for, and characteristics of the triple helical association. Nucleic Acids Res. 27: 695-702.
•Blume, S.W., Guarcello, V., Zacharias, W. & Miller, D.M. (1997) Divalent transition metal cations counteract potassium-induced quadruplex assembly of oligo(dG) sequences. Nucleic Acids Res. 25: 617-625.