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Gary D. Kao, M.D., Ph.D.
Associate Professor, Dept of Radiation Oncology
Cancer Biology Program
Address
180 H John Morgan Bldg.
3620 Hamilton Walk
Philadelphia, PA 19104
Office tel.: 215 573-5503
Lab tel.: 215 573-2285
Fax: 215 573-8769
E-mail: kao@xrt.upenn.edu
Education
Johns Hopkins School of Medicine:
MD, 1988.
University of Pennsylvania: PhD, 1998.
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Research
Interests
- The overall goal of the Kao Laboratory is to understand aspects of cancer and normal cell biology that will ultimately allow us develop and refine anticancer treatment. We are attacking this goal via two interrelated approaches: (i) investigating the biology of histone deacetylases in cancer and normal tissues, its role in development and cellular growth, and in the response to histone deacetylase inhibitors and other treatment modifiers (ii) developing novel vertebrate-based systems to investigate the relative effects of treatment on cancer cell viability as well as normal tissue development and function. We believe the understanding resulting from these investigations will enable us to optimize the "therapeutic ratio" --developing more effective yet less toxic treatment strategies.
Key words: histone deacetylases (HDAC), cancer cytotoxicity,
mitotic progression, radiation and DNA damage
Search PubMed for articles
Description
of Research
Specific Projects in the Kao Laboratory:
Expression and function of Class II histone
deacetylases (HDACs) such as HDAC4. HDACs
are best known for the ability to deacetylate specific lysines
in the tails of core histones, thereby contributing to chromatin
remodeling. These enzymes are intimately involved in diverse
activities including carcinogenesis, gene expression, cell
cycle control, differentation, and much more. HDAC inhibitors
are currently being intensely studied in clinical trials,
including for treating cancer. The HDACs are divided into
classes based on sequence homology. The Class II HDACs,
which include HDAC4, are especially intriguing because it
is increasingly apparent that the target(s) of these enzymes
may extend to nonhistone proteins, with diverse and complex
mechanisms of function and regulation. For example, caspase
mediated cleavage of HDAC4 generates a bioactive amino-terminal
fragment that may not even need its deacetylase domain to
affect the expression of downstream targets. The regulation
of HDAC4 in term may involve mRNA and protein instability,
as well as the Sp1-family of transcription factors. These
mechanisms together may facilitate precise control of its
regulatory functions (i.e. HDAC4 can be quickly turned “off”
and “on”). In addition to its role in controlling gene expression
and viability of cancer cells, HDAC4 has also been linked
to the development of normal tissues such as the CNS, cardiac
and musculoskeletal. However, how HDAC4 expression is regulated
during development is unknown and is one of our current
interests.
Defining the effects of novel anti-cancer
treatment strategies on cancer cell viability and normal tissue
development. The ideal anticancer treatment
combines high efficacy with the least amount of toxicity to
normal tissues. Ionizing radiation (IR, i.e. radiation therapy
or radiation oncology) is a treatment that the majority of
cancer patients will receive at some point in their lives.
In most cases, the treatment is successful and incurs few
or no complications. Complications do occur sometimes and
vulnerable populations such as children are at higher risk.
Surprisingly little is known, however, regarding the pathogenesis
of such complications. Our goal is to develop novel vertebrate
model systems with which to investigate the efficacy and normal
tissue effects of anticancer treatment. We have helped pioneer
the zebrafish (danio rerio) for such studies, especially those
involving IR. The zebrafish offers logistical, technical,
genetic and physiological advantages, which include but are
not limited to: high genetic and physiologic homology to mammals,
rapid development, optical clarity, experimental accessibility
of the embryo and juveniles and opportunities for genetic
and biochemcial screens and manipulations
High-throughput screening for novel compounds
via zebrafish embryos. The low cost, easy care,
and small dimensions of the zebrafish embryo renders it the
ideal (and perhaps the only) vertebrate amenable to high-throughput
screening (HTS). Up to 20 embryos can easily fit within individual
wells of a 96-well microplate. The aqueous environment of
the zebrafish faciliates drug treatment and uniform radiation
dosimetry.
You are most welcome to write, call, or visit us. We'd
love to show you what we do! –
Recent
Publications
Rajendran R, Kao GD. (2007) “No turning
Bax” in the combined battle against prostate cancer. Clinical
Cancer Research, Jun 15;13(12):3435-8.
Lally BE, Geiger G, Kridel S, Wheeler K, Peddi
P, Georgakilas A, Kao GD, Koumenis C. (2007) Identification
and preclinical characterization of a novel and potent small
molecule radiation sensitizer via an unbiased screen of a
chemical library. Cancer Research, Cancer Res.
Sep 15;67(18):8791-9.
Kao GD, Jiang Z, Fernandes
AM, Gupta AK, Maity A. Inhibition of PI3K/Akt signaling impairs
DNA repair in glioblastoma cells following ionizing radiation.
J Biol Chem., 2007 Jul 20;282(29):21206-12.
Huang H, Feng J, Famulski J, Rattner JB, Liu
ST, Kao GD, Muschel R, Chan GKT, Yen TJ. (2007)
Tripin/hSgo2 recruits MCAK to the inner centromere to correct
defective kinetochore attachments. J Cell Biol.,
May 7;177(3):413-24.
Cengel KA, Voong KR, Chandrasekaran S, Maggiorella
L, Brunner TB, Stanbridge E, Kao GD, McKenna
WG, Bernhard EJ. (2007) Oncogenic K-Ras signals through epidermal
growth factor receptor and wild-type H-Ras to promote radiation
survival in pancreatic and colorectal carcinoma cells. Neoplasia.
Apr;9(4):341-8.
Lab
Rotation
Projects
The Kao Laboratory employs a full gamut of genetic, biochemical,
cellular, and developmental techniques. Our published and
ongoing projects have utilized but have not been limited to:
Luciferase and beta-galactosidase-based Reporter assays
Site-directed mutagenesis
Chromatin immunoprecipitation and deletion analyses
Cell-cycle synchrony and cell cycle analyses
Inducible protein expression systems
Immunofluorescence of subcellular structures and immunohistochemical
analyses of clinical tissues
Zebrafish as a vertebrate-model to dissect gene and protein
function in development (through collaboration with the Granato
and Mullins Labs).
- Lab Personnel:
Adegoke Adeniji- Visiting Graduate Student
Vince Bakanauskas- Lab Manager
Melissa Dowling- Lab Manager, Webmaster
Weili Fu, MD- Research Specialist
Geoffry Geiger- Medical Student
Mijin Kim, PhD- Postdoctoral Fellow
Fang Liu, MD- Research Specialist
Ranh Voong- Research Specialist
Stephanie Yee- Undergraduate Student
Frances Lee- Undergraduate
Student
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