Rebecca S. Hartley, Ph.D. is an Associate Professor of Cell Biology and Physiology at the University of New Mexico School of Medicine and a Member of the UNM Cancer Center. She earned her BS in Biology, also from the University of New Mexico, and her doctorate in Biological Structure (Anatomy) from the University of Washington in 1992, studying the developmental origin of adult skeletal muscle stem cells. Professor Hartley completed her postdoctoral studies at the University of Colorado Health Sciences Center and the University of Rennes, France. During this time she began studies on developmental regulation of the embryonic cell cycle, focusing first on post-translational and then post-transcriptional regulatory mechanisms. In1998, she joined the faculty at the University of Iowa where her group described zygote-mediated deadenylation of maternal cyclin mRNAs as a key mechanism of embryonic cell cycle remodeling. Prof. Hartley received a March of Dimes Basil O’Connor Award and an American Cancer Society Research Scholar Award for this work. She continued these studies with an NIH-NCI R01 after her move back home to New Mexico; collaborating with Professors James Dahlberg and Elsebet Lund to show that a zygote transcribed microRNA mediates maternal cyclin deadenylation. Her studies of the Xenopus laevis embryonic cell cycle led directly to her current studies on post-transcriptional regulation of the breast cancer cell cycle. Prof. Hartley’s work has shown that the RNA binding proteins and microRNAs that regulate maternal cyclins are deregulated in breast cancer cells, leading to cyclin overexpression and cell cycle disruption.
The goal of our laboratory is to define post-transcriptional mechanisms of cell cycle regulation in the early embryonic cell cycle of Xenopus laevis and in the cancer cell cycle. We study RNA binding proteins and microRNAs, post-transcriptional regulators responsible for regulating the early embryonic cell cycle, and whose expression is disrupted in cancer. Specifically, we are assessing the role of Human antigen R (HuR), cold-inducible RNA binding protein (CIRP) and microRNAs in co-reulating targets implicated in breast cancer etiology.
The long term goal of the Principal Investigator's laboratory is to understand how the cell cycle is regulated during the development of a multicellular organism. Ultimately, we wish to apply this knowledge to developing novel therapies for cancer and genetic diseases. Towards this goal, we are analyzing gap phase and checkpoint addition to the mitotic cell cycles of Xenopus laevis. Gap phases (G1 and G2) are important periods in the adult somatic cell cycle during which correct replication and division of the chromosomes are ensured. The first gap phase (G1) is also when cells grow, and either commit to another round of cell division or exit the cell cycle, to become quiescent or differentiate. Xenopus laevis embryonic cell cycles lack G phases. The first 12 rapid and synchronous divisions alternate between DNA synthesis and mitosis, and are driven by maternal mRNAs and proteins stored in the egg. The cell cycle remodels after the twelfth divison, lengthening as G phases are added during the switch from maternal to zygotic control of development, the maternal to zygotic transition (MZT). After the MZT in Xenopus, an increase in the length of S-phase extends cycles 13 and 14. Cycle 15 resembles a typical adult somatic cell cycle, with G1 and G2 phases. Cell cycle times now range from 3 to 6 hours, differing for subpopulations of cells in specific regions of the embryo. This natural process of G phase and checkpoint addition to the cell cycle is the converse of the pathway normal cells traverse in becoming cancer cells. Thus, cell cycle remodeling (lengthening due to G phase addition) provides a unique opportunity to study the establishment of controls in a normal and homogeneous cell population. Insight into this process may lead to novel strategies not only to combat uncontrolled cell division, but to prevent mutations leading to neoplastic and malignant states. In addition, identification of novel regulatory mechanisms will result in a better understanding of how the acquisition of a regulated cell cycle is integrated with development.
The mechanism of G-phase addition is unknown, but cell cycle remodeling is associated with dramatic changes in cell cycle regulators. We are studying the mechanisms of these changes. Maternal cyclins and cyclin dependent kinases (cdks), like their somatic counterparts, drive progression through the cell cycle. In somatic cell cycles, cyclin E is synthesized during G1, and cyclin E/Cdk2 kinase activity is rate limiting for progression through S phase, after which cyclin E is degraded. Unlike somatic cycles, in embryonic cycles cyclin E1 is present at constant levels, until it is degraded after the twelfth cell cycle, at the MZT. We believe that constant levels of cyclin E1 during the first 12 cycles eliminate G1 phase, and its degradation is necessary for the addition of G1 after the MBT. We are currently determining the mechanism of cyclin E1 stability during the early cycles, as well as its degradation at the MZT using both in vivo expression and in vitro degradation assays. Degradation of maternal cyclins A1 and B2 follows that of cyclin E1, as does the upregulation of zygotic cyclin A2 and Xic1. Cyclin A2 is the Xenopus homolog of somatic cyclin A, and Xic1 is a member of the p27 family of cyclin dependent kinase inhibitors that specifically inhibits cyclin E/Cdk2. Injection of Xic1 before the MZT lengthens the mitotic cell cycles, and delays the degradation of maternal cyclins and the MZT. These results suggest that cyclin E1/Cdk2 regulates cell cycle length and remodeling, as well as the timing of the MZT. We are testing whether the changes in gene expression that occur during cell cycle remodeling are dependent on repression of cyclin E1/Cdk2.
In addition, we are determining the role of translational control in modulating expression of cyclins and cdk inhibitors during cell cycle remodeling. Current studies focus on identifying and isolating novel regulatory elements in the untranslated regions of mRNAs encoding cell cycle regulators and their interacting RNA-binding proteins. Using these approaches, translation of specific cell cycle proteins can be altered in vivo to determine the role of translational control in cell cycle regulation and remodeling. Linking translational control to cell cycle regulation will suggest pathways that may be altered during tumorigenesis as well as therapeutic targets.
-B.S., University of New Mexico, Albuquerque, NM (Biology), 1986 , 2007-Present , 2007-2009 , 2007 , 2009 ,
2009-Present , 2010-Present
-Ph.D., University of Washington, Seattle, WA (Biological Structure), 1992
-Fellow, HHMI, University of Colorado, Denver, CO, 1992-1996
-Fellow, University of Rennes, Rennes, France, 1996-1997
Assistant -Professor, Anatomy and Cell Biology, University of Iowa School of Medicine, 1998-2002
-Presidential Scholar, University of New Mexico, 1982-1986
-Minority Biomedical Research Support Fellowship, 1985-1986
-Minority Graduate Opportunity Fellowship, University of Washington, 1986-1988
-NIH Developmental Biology Predoctoral Trainee, 1988-1992
-Human Frontiers Science Organization Program Long Term Fellowship 1996-1998
-Assistant Professor, Department of Cell Biology and Physiology, UNM Health Sciences Center, 2002-2006
- Full Member, University of New Mexico Cancer Center, Breast Cancer Multidisciplinary and Protocol Development Subgroups, 2003-Present
- Associate Professor, Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center
- Ad-Hoc Member, Molecular Oncogenesis Study Section, NCI-NIH
-Ad-Hoc Member, Tumor Microenvironment Study Section, 2011
Xun Guo, Postdoctoral Fellow
Audic Y, Garbrecht M, Fritz B, Sheets MD, Hartley RS. Zygotic control of
maternal cyclin A1 translation and mRNA stability.
Dev Dyn. 2002 Dec;225(4):511-21.
Rebecca Hartley, Valerie Le Meuth-Metzinger, and H Beverley Osborne. Screening for sequence-specific RNA-BPs
by comprehensive UV crosslinking.
BMC Molecular Biology. 2002 Jun; 3:8.
Audic Y, Boyle B, Slevin M, Hartley RS. Cyclin E morpholino delays embryogenesis in Xenopus.
Genesis. 2001 Jul;30(3):107-9.
Audic Y, Anderson C, Bhatty R, Hartley RS. Zygotic regulation of maternal cyclin A1 and B2 mRNAs.
Mol Cell Biol. 2001 Mar;21(5):1662-71.
Hartley RS, Sible JC, Lewellyn AL, Maller JL. A role for cyclin E/Cdk2 in the timing of the midblastula
transition in Xenopus embryos.
Dev Biol. 1997 Aug 15;188(2):312-21.
Hartley RS, Rempel RE, Maller JL. In vivo regulation of the early embryonic cell cycle in Xenopus.
Dev Biol. 1996 Feb 1;173(2):408-19.
Haccard O, Lewellyn A, Hartley RS, Erikson E, Maller JL. Induction of Xenopus oocyte meiotic maturation by MAP kinase.
Dev Biol. 1995 Apr;168(2):677-82.
Hartley RS, Lewellyn AL, Maller JL. MAP kinase is activated during mesoderm induction in Xenopus laevis.
Dev Biol. 1994 Jun;163(2):521-4.
Guo, X and RS Hartley. (2006). HuR contributes to cyclin E mRNA deregulation in MCF-7 breast cancer cells. Canc. Res. 66:7948-7956. PMID: 16912169
Slevin, M, F. Gourronc, and RS Hartley. (2007). ElrA binding to the 3’UTR of cyclin E1 mRNA requires polyadenylation elements. NAR 35:2167-2176. PMID: 17355986
Guo, X, F Gourronc, Y Audic, G Lyons-Levy, T Mitchell and RS Hartley. (2008). ElrA and AUF1 differentially bind the cyclin B2 mRNA. Biochem. Biophys. Res. Com. 377, 653-65. PMID: 18930026
Hartley, RS. (2008). Regulating the regulators: control of cyclin mRNA decay. In: Trends in Cell Cycle Research. Kenichi Yoshida, Ed. Research Signpost, Kerala, India. 261-275.
Guo, X, Y Wu and RS Hartley. (2009). MicroRNA-125a represses cell growth by targeting HuR in breast cancer. RNA Biol. 6:575-583. PMID: 19875930
Lund, E, M Liu, RS Hartley, MD Sheets, and J Dahlberg. (2009). Deadenylation of maternal mRNAs in mediated by miR-427 in Xenopus laevis embryos, RNA 15:2351-2363 PMID: 19854872
Guo, X, Y Wu and RS Hartley. (2010). Cold-inducible RNA binding protein contributes to HuR and cyclin E1 deregulation in breast cancer cells. Mol. Carc. 49:130-140. PMID: 19777567
Almeida, AD, HM Wise, CJ Hindley, MK Slevin, RS Hartley, and A Philpott. (2010). The F-box protein Cdc4/Fbxw7 is a novel regulator of neural crest development in Xenopus laevis. Neural Dev. 5:1. PMID: 20047651
Sheets, MD, B Fritz, RS Hartley, and Y Zhang. (2010). Polyribosome analysis for investigating mRNA translation in Xenopus oocytes, eggs and embryos. Methods, epublished Jan 22. PMID: 20096782
Guo, X. and RS Hartley, 2010. MicroRNA-RNA binding protein face-off in cancer. Cell Cycle 9(7): epubished Apr 1. PMCID: in process
Wu, Y, X Guo, Y Brandt, HJ Hathaway, and RS Hartley. (2010). Three-dimensional collagen represses cyclin E1 via beta one integrin in invasive breast cancer cells. Breast Cancer Res. Treat. Epublished Jul 4. DOI 10.1007/s10549-010-1013-x. PMCID: in process
Brandt, Y, T Mitchell, Y Wu and RS Hartley. 2011. Developmental downregulation of cyclin E1 is phosphorylation and nuclear import dependent and is mediated by ubiquitination. Dev. Biol. In press.