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Faculty
 Christopher D. Heinen
Assistant Professor of Medicine
cheinen@uchc.edu
Areas of Interest:
Colon cancer is the third most common malignancy in men and women and
ranks behind only lung cancer in cancer deaths. The most common
hereditary disease that predisposes patients to colorectal cancer is
hereditary non-polyposis colon cancer (HNPCC) which stems from mutations
in the mismatch repair (MMR) genes. In addition to its role in HNPCC,
flawed MMR has been implicated in 15-40% of sporadic colorectal and
other extracolonic tumors indicating a more general role for MMR in
tumor protection. Although many functional details of the MMR proteins
have emerged, the mechanism by which flawed MMR contributes to
tumorigenesis is not fully understood. Faulty MMR results in an elevated
mutation rate (mutator phenotype), which has been proposed to lead to an
accumulation of oncogene and tumor suppressor mutations that ultimately
cause cancer. More recent work has revealed that MMR proteins play an
important role in cell cycle arrest and apoptosis in response to certain
DNA damaging agents. Thus, MMR mutations may affect tumorigenesis
through multiple mechanisms. Our laboratory is interested in
understanding what functions of the MMR system are affected during
tumorigenesis.
We are addressing this broad question through a multi-pronged
approach. First, we are examining how the biochemical and biophysical
properties of MMR proteins are affected by cancer-associated missense
mutations. Missense mutations of at least two MMR genes hMSH2 and hMSH6
have been linked to HNPCC families providing a tool whereby full-length
proteins with single amino acid alterations can be studied to determine
how these alterations affect function. The hMSH2 and hMSH6 proteins form
heterodimers in cells that recognize DNA lesions and initiate the repair
process. Our laboratory utilizes purified human hMSH2-hMSH6 heterodimers
in a series of in vitro biochemical and biophysical assays to learn
about the normal biochemical mechanism as well as the consequences of
cancer-associated mutations on this mechanism. Secondly, we are
examining the cellular functions of the MMR proteins and the effects of
cancer-causing missense mutations by studying how these mutant proteins
perform in DNA repair, cell cycle checkpoint signaling, apoptosis
signaling and other functional assays. Finally, we are interested in
identifying proteins that interact with the normal MMR proteins and in
determining how these interactions are affected during tumorigenesis.
Lab Rotation Projects:
The research in my laboratory involves an array of techniques from
biochemistry to cell biology to animal models to address the fundamental
question of why mutations in DNA mismatch repair genes cause cancer. We
are predominantly interested in using cancer-associated missense
mutations of the hMSH2 and hMSH6 genes to understand the functions of
mismatch repair affected during colorectal tumorigenesis. Projects
include:
- Biochemical and biophysical characterizations of the wild-type and
mutant hMSH2-hMSH6 heterodimers…
- Using cell culture models to study the functions of mutant hMSH2
and hMSH6 in damage repair and response...
- Examining the pre-neoplastic colorectal lesions aberrant crypt
foci for defects in mismatch repair...
Other projects available and can be discussed depending on student’s
interest.
Selected Publications:
Stevens, RG, Swede, H, Heinen, CD, Jablonski, M, Grupka, M, Ross, B,
Parente, M, Tirnauer, JS, Giardina, C, Rajan, TV, Rosenberg, DW and
Levine, J. Aberrant Crypt Foci in patients with a positive family
history of sporadic colorectal cancer. 2007. Cancer Letters. In Press.
Greenspan, EJ, Cyr, JL, Pleau, DC, Levine, J, Rajan, TV, Rosenberg,
DW and Heinen, CD. Microsatellite instability in aberrant crypt foci
from patients without concurrent colon cancer. 2007. Carcinogenesis. In
Press.
Rosenberg, DW, Yang, S, Pleau, DC, Greenspan, EJ, Stevens, RG, Rajan,
TV, Heinen, CD, Levine, J and O’Brien, MJ. Mutations in BRAF and KRAS
differentially distinguish serrated vs. non-serrated hyperplastic
aberrant crypt foci in humans. 2007. Cancer Research. In Press.
Shim K-S, Schmutte C, Tombline G, Heinen CD, Fishel R. hXRCC2
enhances ADP/ATP processing and strand exchange by hRAD51. 2004. Journal
of Biological Chemistry. 279:30385-30394.
Tombline G, Heinen CD, Shim K-S, Fishel R. Biochemical
characterization of the human RAD51 protein: III. Modulation of DNA
binding by adenosine nucleotides. 2002. Journal of Biological Chemistry
277:14426-14433.
Heinen CD, Wilson T, Mazurek A, Berardini M, Butz C, Fishel R. HNPCC
mutations in hMSH2 result in reduced hMSH2-hMSH6 molecular switch
functions. 2002. Cancer Cell 1:469-478.
Heinen CD, Schmutte C, Fishel R. DNA repair and tumorigenesis:
lessons from hereditary cancer syndromes. 2002. Cancer Biology and
Therapy 1:477-485.
Heinen CD, Goss KH, Cornelius JR, Babcock GF, Knudsen ES, Kowalik T,
Groden J. The APC tumor suppressor controls entry into S-phase through
its ability to regulate the cyclin D/RB pathway. 2002. Gastroenterology
123:751-763. |
