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Chris Quirk Lab
Research Interests
Deciphering the Role of
p8 in Development, Tumorigenesis, and Malignancy
Our research
is focused on investigating the mechanisms of
tumor initiation and progression. We have shown
that the high mobility group (HMG) A family
member p8 is a mediator of tumorigenic
potential in a genetically-defined model of
tumorigenesis, the LβT2 cell line. p8 appears
to play a direct role in oncogenesis, however;
the mechanism by which it promotes cellular
change is unknown. We
hypothesize that p8 facilitates genomic
instability through altering cell cycle check
points and that inhibition of p8 represents a
novel mechanism by which tumor initiation and/or
growth can be curtailed. The cell cycle is
a complex process during which cells grow,
replicate their genomes, and divide. Strict
regulation of the cell cycle is necessary for
the health of all cellular organisms and loss of
cell cycle regulation often results in abnormal
cell proliferation and cancer. Checkpoints
within the cell cycle ensure that cell
proliferation occurs in an orderly manner. One
key checkpoint, the G1-to-S transition, is a
vital regulatory stage after which the cell is
committed to division. Critical to regulation
of this transition are the cyclins and cyclin-dependent
kinases (cdks), which associate to form
heterodimeric complexes. The candidate tumor
suppressor p27 is a cdk inhibitor that plays a
vital role in the cell cycle by inhibiting the
interaction between cyclin E and cdk2 and
blocking the transition from G1-to-S phase. p27
levels are strictly controlled throughout the
cell cycle by Jun activating binding protein 1
(Jab1). During G1, Jab1 dissociates from a
large nuclear complex, binds p27, and mediates
p27 export from the nucleus and degradation by
the 26S proteasome, thus allowing for cell cycle
progression. Recently the protein p8 was found
to play a vital role in Jab1-mediated p27
degradation; however, the mechanisms by which p8
encourages p27 breakdown through its interaction
with Jab1 is unknown. Our goal is to elucidate
the mechanism by which p8 acts with Jab1 to
facilitate p27 degradation, thus stimulating
cell cycle progression. Ultimately, our long
term goal will be to design strategies to
utilize control of p8 and its signaling network
as a tool in targeted therapy to control tumor
growth.
Selected
Publications:
Keri,
R.A., D.J. Bachmann, A. Behrooz, B.D. Herr, R.K.
Ameduri, C.C. Quirk, and J.H. Nilson.
(2000) An NF-Y binding site is important for
basal, but not gonadotropin-releasing
hormone-stimulated, expression of the
luteinizing hormone β subunit gene. The
Journal of Biological Chemistry 275:
13082-13088.
Quirk, C.C.
and J.H. Nilson. (2000) Hormones and gene
expression: Basic principles. DeGroot and
Jameson’s Endocrinology. 4th
Edition. W.B. Saunders Company, Philadelphia,
Pennsylvania, pp 3-13.
Nilson,
J.H., R.A. Abbud, R.A. Keri, and C.C. Quirk.
(2000) Chronic hypersecretion of LH in
transgenic mice disrupts both ovarian and
pituitary function with some effects modified by
the genetic background. Recent Progress in
Hormone Research, 55: 69-91.
Quirk, C.C.,
K.L. Lozada, R.A. Keri, and J.H. Nilson.
(2001) A single Pitx1 binding site is essential
for activity of the LHβ promoter in transgenic
mice. Molecular Endocrinology 15:
734-746.
Quirk, C.C.,
D.D. Seachrist, and J.H. Nilson. (2003)
Embryonic expression of the luteinizing hormone
β gene appears to be coupled to the transient
appearance of p8, a high mobility group-related
transcription factor. The Journal of
Biological Chemistry 278: 1680-1685.
Mohammad, H.P., D.D. Seachrist, C.C. Quirk,
and J.H. Nilson. (2004) Re-expression of
p8 contributes to tumorigenic properties of
pituitary cells and appears in a subset of
prolactinomas in transgenic mice that
hypersecrete LH. Molecular Endocrinology
18: 2583-2593.
Jorgensen, J.S., C.C. Quirk, and J.H.
Nilson. (2004) Multiple and overlapping
combinatorial codes orchestrate hormonal
responsiveness and dictate cell-specific
expression of the genes encoding LH.
Endocrine Reviews 25: 521-542 (cover
article).
Quirk, C.C.
and J.H. Nilson. (2005) Hormones and gene
expression: Basic principles. DeGroot and
Jameson’s Endocrinology. 5th
Edition. W.B. Saunders Company, Philadelphia,
Pennsylvania, pp 17-28.
Million Passe, C.M., G. Cooper, and C.C.
Quirk. (2006) The murine p8 gene is
activated by activating transcription factor 4
in LβT2 cells. Endocrine 30: 81-91.
PhD: Colorado
State University, Animal Reproduction and
Biotechnology Laboratory, 1997
Postdoctoral Fellowship: Case Western Reserve
University School of Medicine, Department of
Pharmacology, 2003
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