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Mark G. Alexandrow, Ph.D. E-mail: Mark.Alexandrow@moffitt.org Phone: 813-745-1450 |
Training
B.A.: University of Virginia, Biology,1991
Ph.D.: Vanderbilt University, 1996
Postdoctoral Fellow: University of Virginia School of Medicine, 1997-2002
Faculty Research Scientist: University of Virginia School of Medicine, 2002-2005
Research
Interests
The research in Dr. Alexandrow's laboratory is focused on two central areas: (1) the mechanisms by which growth factor signals, or inhibitory TGF-beta signals and the Ras-Rb pathway, regulate the assembly and function of pre-(DNA) Replication Complexes (preRCs) in late G1 phase, and (2) how the DNA replication machinery and preRCs utilize chromatin remodeling complexes to gain access to the DNA substrate during late G1 and S-phase. The long term goal of this research is to understand the cell cycle regulation of preRC function and assembly in late G1 by growth factors and Rb/E2F, and identify potentially novel protein-protein interactions and key regulatory steps that might serve as useful targets for small molecule drug design for the treatment of cancer.
Dr. Alexandrow has identified a genetic interaction between Ras and one preRC subunit, Mcm7, in which ectopic expression of Mcm7 suppresses grow inhibition induced by a dominant-negative Ras allele and elicits a transformed morphology in cultured mouse cells. Studies are underway to determine the mechanism of this Ras-Mcm7 interaction, and how the Ras-Rb pathway is involved, perhaps directly, in preRC regulation prior to the G1/S transition. Toward this end, it is already known that Mcm7 physically binds both Rb and cyclin D1, the latter of which is complexed to the Rb-inactivating kinase, Cdk4. Thus, Mcm7 may be at the center of a pivotal pathway in late G1 that involves Rb-mediated preRC regulation. Since TGF-beta induced growth-inhibitory signals are known to be mediated by Rb, another aspect of this project will focus on how and if TGF-beta signals affect preRC function through Rb-Mcm7 interactions. In this manner, novel targets of TGF-beta signaling may be found that might explain how TGF-beta can block entry into S-phase in the latter few hours of G1-phase.
Another study by Dr. Alexandrow has identified a novel mechanism by which the DNA replication machinery opens condensed chromatin during S-phase progression to facilitate fork movement. Using a novel in vivo chromatin-remodeling system, a replication fork protein, Cdc45, was shown to be capable of inducing large-scale chromatin decondensation mediated by recruitment of Cdk2 and linker histone (H1) phosphorylation. The phosphorylation of H1 is known to be involved in higher-order chromatin folding, and it is likely that Cdc45-Cdk2-mediated H1 phosphorylation mediates chromatin unfolding at replication forks during S-phase progression. Preliminary data from the Alexandrow laboratory suggests that many other preRC subunits are capable of inducing chromatin remodeling in this in vivo system, and studies are currently underway to determine the mechanisms by which these other preRC subunits cause chromatin decondensation. The lab is also interested in whether chromatin-associated Rb and E2F may modify or regulate any chromatin remodeling at origins of replication.
Search
for publications by: 
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search will be conducted at the US National Library of Medicine (NLM) and PubMed.
Selected
Publications
1. Mark G. Alexandrow and Joyce L. Hamlin. 2005. Chromatin Decondensation In S-Phase Involves Recruitment of Cdk2 by Cdc45 and Histone H1 Phosphorylation. J. Cell Biology, 168:875-886. (including ‘In This Issue’ article).
2. Mark G. Alexandrow and Joyce L. Hamlin. 2004. Cdc6 Chromatin Affinity Is Unaffected by Serine-54 Phosphorylation, S-phase Progression, and Overexpression of Cyclin A. Mol. Cell. Biol., 24:1614-1627.
3. Mark G. Alexandrow, Marion Ritzi, Alexander Pemov, and Joyce L. Hamlin. 2002. A Potential Role for Mini-Chromosome Maintenance (MCM) Proteins in Initiation at the Dihydrofolate Reductase Replication Origin. J. Biol. Chem., 277:2702-2708.
4. Mark G. Alexandrow and Harold L. Moses. 1995. Transforming Growth Factor ß1 Inhibits Mouse Keratinocytes Late in G 1 Independent of Effects on Gene Transcription. Cancer Res., 55:3928-3932.
5. Mark G. Alexandrow and Harold L. Moses. 1995. TGFß and Cell Cycle Regulation. Cancer Res., 55:1452-1457.
Cancer Biology Ph.D. Program
H. Lee Moffitt Cancer Center, MRC-4 East
12902 Magnolia Drive
Tampa, Florida 33612
Phone: 813-745-6876
E-mail: CancerPHD@moffitt.org
Copyright © 2000 University of South Florida