User:Anna Marie Kenney
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Revision as of 13:30, 21 August 2013
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Anna Marie Kenney
- Associate Professor
- Department of Pediatric Oncology, Winship Cancer Institute and Center for Children's Neuroscience Research
- 1760 Haygood Dr NE, Lab E397
My research focuses on cell cycle control in cerebellar development and medulloblastoma, a pediatric brain tumor that arises in the cerebellum. These tumors are the most common solid malignancy of childhood. Current treatments for medulloblastomas include surgical resection, chemotherapy, and cranio-spinal irradiation. These therapies lead to an ~60% "cure" rate, but survivors are left with life long devastating side effects as a result of these treatment, including cognitive declines, seizures, developmental delays, and premature aging. It is our hope that by gaining increased insight into the cellular and molecular mechanisms that drive tumor establishment and growth, we can identify genes and proteins whose activity could in the future be modulated by drugs and novel small molecules, thereby ameliorating the need for irradiation and chemotherapy.
Medulloblastomas can be divided into four molecularly and histologically distinct subclasses, one of which is typified by activation of a pathway called Sonic hedgehog (SHH). This subclass is proposed to arise from rapidly proliferating cerebellar neural precursors, which depend on Shh for their cell division during development. We study how Shh drives proliferation through its interactions with other developmentally regulated pathways, such as the Hippo pathway, insulin-like growth factor (IGF) pathway, and the mTOR pathway, which drives new protein synthesis in response to growth factor signaling.
The workhorse of the lab is primary cerebellar cultures derived from the neonatal mouse cerebellum. These cells can be maintained in culture in serum free medium; the addition of purified Shh to the medium maintains them in a proliferative state for approximately 72 hours. We can manipulate the cells pharmacologically or genetically (using retroviruses and shRNA-carrying lentiviruses) and observe effects on proliferation and pathway activation using common cell biological techniques. These studies are complemented with histological analysis of the developing cerebellum. We also use mice that have been genetically modified so that the Shh pathway is constitutively activated in the developing cerebellum. These mice develop medulloblastomas that closely resemble those of the human subclass of medulloblastoma associated with activated Shh signaling. Current projects in the lab involve conditionally inactivating components of the Hippo and IGF2 pathway, which we have previously found to cooperate with Shh mitogenic and oncogenic effects, in these mice to determine impact on tumor latency and survival.
- 1998-2003, Postdoc, Dana-Farber Cancer Institute/Harvard Medical
- 1998, PhD, Yale University, New Haven, Connecticut
- 1991, BA, St. Mary’s College, St. Mary’s City, Maryland
- Interest 1
- Interest 2
- Interest 3
- 1. Kenney, AM and Rowitch, DH. Sonic hedgehog promotes G1 cyclin expression and sustained cell
cycle progression in mammalian neuronal precursors. Molecular and Cellular Biology 20:9055-9067. (2000)
- 2. Ciemerych MA, Kenney AM, Sicinska E, Kalaszczynska I, Bronson RT, Rowitch DH, Gardner H, and
Sicinski P. Development of mice expressing a single D-type cyclin. Genes and Development, 16:3277- 89 (2002)
- 3. Kenney, AM, Cole MD, and Rowitch, DH. N-myc upregulation by Sonic hedgehog promotes
proliferation in developing cerebellar granule neuron precursors. Development 130: 15-28. (2003) Selected for “highlight” in Nature Reviews Neuroscience (January 2003).
- 4. Kenney, AM, Widlund, HR, and Rowitch, DH. Hedgehog and PI-3 kinase signaling converge upon Nmyc
to promote cell cycle progression in cerebellar neuronal precursors. Development 131: 217-228 (2004).
- 5. Sjostrom, S, Finn, G, Hahn WC, Rowitch, DH, and Kenney, AM. Cdk1 plays a prime role in regulating
N-myc phosphorylation and turnover in neural precursors. Developmental Cell 9:327-338 (2005).
- 6. Kenney, AM*, Browd SR*, Gottfried, ON, Pedone, CA, Fults, DW. N-myc substitutes for IGF signaling
in a mouse model of Sonic hedgehog-induced medulloblastoma formation. Cancer Research 66: 2666- 2672 (2006). *co-first authors
- 7. Parathath SR*, Mainwaring LA*, Fernandez-L A, Campbell DO, and Kenney AM. Insulin receptor
substrate1 is an effector of Sonic hedgehog mitogenic signaling in cerebellar neural precursors. Development 135: 3291-3300 (2008). PMC2673703 *co-first authors
- 8. Bhatia B, Northcott PA, Hambardzumyan D, Govindarajan B, Brat DJ, Arbiser JA, Holland EC, Kenney
AM. Tuberous sclerosis complex suppression in cerebellar development and medulloblastoma: separate regulation of mTOR activity and p27kip1 localization. Cancer Research 69: 7224-7234 (2009). PMC2745891
- 9. Fernandez-L A, Northcott PA, Dalton J, Fraga C, Ellison D, Taylor MD, Kenney AM. YAP1 is amplified
and up-regulated in hedgehog-associated medulloblastomas and mediates Sonic hedgehog-driven neural precursor proliferation. Genes and Development, 23: 2675-2692 (2009). PMC2788333
- 10. Mainwaring, LA and Kenney, AM. Divergent functions for eIF4E and S6 kinase downstream of Sonic
hedgehog mitogenic signaling in the developing cerebellum. Oncogene, 30 (15): 1784-97 2011.
- 11. Fernandez-L A, Squatrito M, Northcott PA, Awan A, Holland EC, Taylor MD, Nahle Z, Kenney AM.
Oncogenic YAP promotes radioresistance and genomic instability in medulloblastoma through IGF2- mediated Akt activation. Oncogene, August 2011
- 12. Northcott PA*, Fernandez-L A*. Hagan JP*, Ellison DW, Grajkowska W, Gillespie Y, Grundy R, Van
Meter T, Rutka JT, Croce CM#, Kenney AM#, Taylor MD#. The miR-17/92 polycistron is up-regulated in Sonic hedgehog-driven medulloblastomas and induced by N-myc in Sonic hedgehog-treated cerebellar neural precursors. Cancer Research 69: 3249-3255 (2009). PMC2836891
- 13. Bhatia B, Malik A, Fernandez-L A, Kenney AM. P27kip1, a Double-edged sword in Shh-mediated
medulloblastoma: tumor accelerator and suppressor. Cell Cycle, 9 (21): 4307-14 2010 14. Parathath S, Mainwaring LA, Fernandez-L A, Guldal CG, Nahle Z, Kenney AM. β-Arrestin-1 links mitogenic Sonic hedgehog signaling to the cell cycle exit machinery in neural precursors. Cell Cycle 9 (19) 2010.
- 15. Bhatia B, Kenney AM, Nahle Z. Mitogenic Sonic hedgehog signaling drives E2F1-dependent
lipogenesis in cerebellar precursor cells and medulloblastoma. Oncogene, 30: (4): 410-22 2011.