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Full Abstracts – CELL DIVISION AND GROWTH CONTROL
172
145
Polyploidy as a mechanism of tissue repair.
Vicki P. Losick
1
, Don T. Fox
2
, Allan C. Spradling
1
. 1) Dept Embryology, HHMI, Carnegie Institution for
Science, Baltimore, MD; 2) Department of Pharmacology and Cancer Biology Duke University Medical Center, Durham, NC.
Wound healing is essential for all organisms to survive. It protects against infection and restores tissue integrity following injury or damage. Many adult
tissues lack active stem cells and in these cases, the cellular mechanisms of tissue repair are not well understood. Adult fruit flies can also recover rapidly
from penetrating injury or genetically induced tissue damage. In response to tissue damage, adult cells reenter the cell cycle and express S phase markers in
at least three distinct tissue types. However, these cells appear to help heal the damaged tissue not by cell division, but by increasing ploidy through
endoreplication. Interestingly, a similar response has been shown to occur in mammalian tissues, particularly the liver, but the mechanism and importance of
endoreplication to the repair program remains poorly understood. The adult fruit fly response may provide insight into a neglected aspect of mammalian
tissue repair where a pre-existing cell can fill the space and function of cells lost to damage.
146
Homeodomain-interacting protein kinase inhibits Hippo signaling to promote growth during
Drosophila
development.
Joanna Chen, Esther
Verheyen. Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.
The Hippo (Hpo) pathway regulates tissue size by controlling cell proliferation and apoptosis. The core components of the Hpo pathway, Hpo, Salvador,
Warts (Wts) and Mats, form a kinase cascade to inhibit the activity of Yorkie (Yki), the transcriptional regulator of the pathway. Inhibition or loss of Hpo
signaling results in massive overgrowth. Here, we identified
homeodomain-interacting protein kinase
(
hipk
) as the first kinase to promote Yki activity in the
Hippo pathway. Hipk encodes a member of a novel family of nuclear protein kinases. Changes in Hipk protein levels affect cell proliferation and apoptosis,
but not cell size, during
Drosophila
wing development. Hipk modulates expression of Hippo targets, such as
ex
-lacZ,
DIAP
-lacZ, Cyclin E and Wg. Our
genetic interaction studies suggest that Hipk functions downstream of Wts and Ex. Moreover, Hipk activity in the Hippo pathway appears to be Yki-
dependent. Our biochemical studies indicate that Hipk interacts with and phosphorylates Yki. Our findings suggest that Hipk is a positive regulator of Yki to
regulate Hpo signaling during
Drosophila
development.
147
Tumor suppression by cell competition through regulation of the Hippo pathway.
Molly C. Schroeder
1,2
, Chiao-Lin Chen
2
, Madhuri Kango-Sing
3
,
Chunyao Tao
2
, Georg Halder
2
. 1) Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030; 2) The University of Texas MD Anderson Cancer
Center, 1515 Holcombe, Houston, TX 77030; 3) University of Dayton, Dayton, Ohio.
Homeostatic mechanisms can eliminate abnormal cells to prevent diseases such as cancer. However, the underlying mechanisms of this surveillance are
poorly understood. Here we investigated how clones of cells mutant for the neoplastic tumor suppressor gene
scribble
(
scrib
) are eliminated from Drosophila
imaginal discs. When all cells in imaginal discs are mutant for
scrib
, then they hyperactivate the Hippo pathway effector Yorkie (Yki), which drives growth
of the discs into large neoplastic masses. Strikingly, when discs also contain normal cells, then the
scrib
cells do not overproliferate and eventually undergo
apoptosis through JNK-dependent mechanisms. However, induction of apoptosis does not explain how
scrib
cells are prevented from overproliferating. We
report that cell competition between
scrib
and wild-type cells prevents hyperproliferation by suppressing Yki activity in
scrib
cells. The suppression of Yki
activation is critical for the elimination of
scrib
clones by cell competition and experimental elevation of Yki activity in
scrib
cells is sufficient to fuel their
neoplastic growth. Thus, cell competition acts as a tumor suppression mechanism by regulating the Hippo pathway in
scrib
cells.
148
The cell adhesion molecule Echinoid functions as a tumor suppressor and upstream regulator of the Hippo signaling pathway.
Tao Yue, Aiguo Tian,
Jin Jiang. Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX.
How multi-cellular organisms control their growth to reach final organ size during development is a fascinating problem in Biology. Recent studies,
initially from Drosophila, have identified an evolutionarily conserved pathway, the Hippo tumor suppressor pathway, as a key mechanism that controls
tissue growth and organ size by simultaneously inhibiting cell growth/proliferation and promoting cell death. The Hpo signaling pathway has also been
implicated in cell contact-dependent growth inhibition, and deregulation of the Hpo pathway has been connected to a wide range of human cancers. The core
pathway consists of the Hpo/Warts (Wts) kinase cassette that phosphorylates and inactivates the transcriptional coactivator Yorkie (Yki). Here, we report
that Echinoid (Ed), an immunoglobulin domain-containing cell adhesion molecule, acts as an upstream regulator of the Hpo pathway. Loss of Ed
compromises Yki phosphorylation, resulting in elevated Yki activity that drives Hpo target gene expression and tissue overgrowth. Ed physically interacts
with and stabilizes the Hpo-binding partner Salvador (Sav) at adherens junctions. Ed/Sav interaction is promoted by cell-cell contact and requires
dimerization of Ed cytoplasmic domain. Overexpression of Sav or dimerized Ed cytoplasmic domain suppressed loss-of-Ed phenotypes. We propose that Ed
may link cell-cell contact to Hpo signaling through binding and stabilizing Sav, thus modulating the Hpo kinase activity.