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1.  Autophagy in oncogenic K-Ras promotes basal extrusion of epithelial cells by degrading S1P 
Current biology : CB  2013;24(1):19-28.
To maintain a protective barrier, epithelia extrude cells destined to die by contracting a band of actin and myosin. Although extrusion can remove cells triggered to die by apoptotic stimuli, to maintain constant cell numbers, epithelia extrude live cells, which later die by anoikis. Because transformed cells may override anoikis and survive after extrusion, the direction of extrusion has important consequences for the extruded cell’s fate. As most cells extrude apically, they are typically eliminated through the lumen, however, cells with upregulated survival signals that extrude basally could potentially invade the underlying tissue and migrate to other sites in the body.
We found that oncogenic K-Ras cells predominantly extrude basally, rather than apically, in a cell-autonomous manner and can survive and proliferate following extrusion. Expressing K-RasV12 down-regulates the bioactive lipid Sphingosine 1-Phosphate (S1P) and its receptor S1P2, both of which are required for apical extrusion. Surprisingly, the S1P biosynthetic pathway is not affected, as the S1P precursor, sphingosine kinase, and the degradative enzymes S1P lyase and S1PP phosphatase are not significantly altered. Instead, we found that high levels of autophagy in extruding RasV12 cells leads to S1P degradation. Disruption of autophagy chemically or genetically in K-RasV12 cells rescues S1P localization and apical extrusion.
Oncogenic K-Ras cells down-regulate both S1P and its receptor S1P2 to promote basal extrusion. Because live basally extruding cells can survive and proliferate following extrusion, we propose that basal cell extrusion provides a novel mechanism for cells to exit the epithelium and initiate invasion into the surrounding tissues.
PMCID: PMC3932369  PMID: 24361067
2.  Cells: shaping tissues and organs 
PMCID: PMC3952838  PMID: 24626844
3.  Bringing balance by force: live cell extrusion controls epithelial cell numbers 
Trends in cell biology  2012;23(4):185-192.
To function as an intact barrier, epithelia must maintain constant cell numbers despite high rates of turnover. If the rate of death exceeds proliferation, epithelial barrier function could become compromised; if it lags behind proliferation, cells could amass into tumors. Although the balance between cell death and division is critical for preventing pathology, most studies focus on each process in isolation. Loss of contact inhibition is a hallmark of cancer cells and cell contacts appear important for linking rates of cell division and death. However, epithelial cells continuously divide and die while maintaining contacts with each other, so other factors must control this balance. Recent studies find that cell crowding forces from cell proliferation can drive cells to die by extrusion from the epithelium. Factors that alter this response to cell crowding may lead to barrier function diseases or promote hyperplasia and cancer.
PMCID: PMC3615095  PMID: 23273931
4.  New emerging roles for epithelial cell extrusion 
Current opinion in cell biology  2012;24(6):865-870.
Epithelia use a unique process called ‘cell extrusion’ to remove cells from a layer, while preserving their barrier function. Specifically, a cell destined to die triggers formation of an actin- and myosin-ring in the live neighboring epithelial cells surrounding it, which squeeze the dying cell out. During extrusion, the surrounding cells expand toward one another and meet to fill the gap left by the extruded cell. Recent studies have revealed new roles of extrusion in controlling developmental morphogenesis, maintaining homeostatic cell numbers, and how this process is usurped during bacterial pathogenesis. Here, we review recent advances in new processes that require cell extrusion and the signaling pathways controlling it.
PMCID: PMC3549431  PMID: 23044222
5.  Programmed Cell Death: A New Way Worms Get Rid of Unwanted Cells 
Current biology : CB  2012;22(19):R844-R846.
The genetics and predictable cell death lineages in Caenorhabditis elegans have been critical for identifying a conserved apoptosis pathway. Yet, cells still die in mutants that disrupt this pathway. A recent study shows that this death occurs by cell shedding.
PMCID: PMC3618969  PMID: 23058805
6.  The tumor suppressor adenomatous polyposis coli controls the direction in which a cell extrudes from an epithelium 
Molecular Biology of the Cell  2011;22(21):3962-3970.
Adenomatous polyposis coli (APC) controls the direction in which cells extrude from epithelia. APC acts in the dying cell to control where microtubules target actomyosin contraction in neighboring cells that squeeze out the dying cell. APC mutations that frequently occur in colon cancer cause cells to extrude aberrantly beneath epithelia, which could enable tumor cell invasion.
Despite high rates of cell death, epithelia maintain intact barriers by squeezing dying cells out using a process termed cell extrusion. Cells can extrude apically into the lumen or basally into the tissue the epithelium encases, depending on whether actin and myosin contract at the cell base or apex, respectively. We previously found that microtubules in cells surrounding a dying cell target p115 RhoGEF to the actin cortex to control where contraction occurs. However, what controls microtubule targeting to the cortex and whether the dying cell also controls the extrusion direction were unclear. Here we find that the tumor suppressor adenomatous polyposis coli (APC) controls microtubule targeting to the cell base to drive apical extrusion. Whereas wild-type cells preferentially extrude apically, cells lacking APC or expressing an oncogenic APC mutation extrude predominantly basally in cultured monolayers and zebrafish epidermis. Thus APC is essential for driving extrusion apically. Surprisingly, although APC controls microtubule reorientation and attachment to the actin cortex in cells surrounding the dying cell, it does so by controlling actin and microtubules within the dying cell. APC disruptions that are common in colon and breast cancer may promote basal extrusion of tumor cells, which could enable their exit and subsequent migration.
PMCID: PMC3204059  PMID: 21900494
7.  Epithelial cell extrusion requires the sphingosine-1-phosphate receptor 2 pathway 
The Journal of Cell Biology  2011;193(4):667-676.
Apoptotic epithelial cells signal to neighboring cells to induce dying cell extrusion by releasing sphingosine-1-phosphate.
To maintain an intact barrier, epithelia eliminate dying cells by extrusion. During extrusion, a cell destined for apoptosis signals its neighboring cells to form and contract a ring of actin and myosin, which squeezes the dying cell out of the epithelium. Here, we demonstrate that the signal produced by dying cells to initiate this process is sphingosine-1-phosphate (S1P). Decreasing S1P synthesis by inhibiting sphingosine kinase activity or by blocking extracellular S1P access to its receptor prevented apoptotic cell extrusion. Extracellular S1P activates extrusion by binding the S1P2 receptor in the cells neighboring a dying cell, as S1P2 knockdown in these cells or its loss in a zebrafish mutant disrupted cell extrusion. Because live cells can also be extruded, we predict that this S1P pathway may also be important for driving delamination of stem cells during differentiation or invasion of cancer cells.
PMCID: PMC3166871  PMID: 21555463
8.  P115 RhoGEF and microtubules decide the direction apoptotic cells extrude from an epithelium 
The Journal of Cell Biology  2009;186(5):693-702.
Communication between microtubules and actin/myosin networks determine epithelial cell extrusion polarity.
To preserve epithelial barrier function, dying cells are squeezed out of an epithelium by “apoptotic cell extrusion.” Specifically, a cell destined for apoptosis signals its live neighboring epithelial cells to form and contract a ring of actin and myosin II that squeezes the dying cell out of the epithelial sheet. Although most apoptotic cells extrude apically, we find that some exit basally. Localization of actin and myosin IIA contraction dictates the extrusion direction: basal extrusion requires circumferential contraction of neighboring cells at their apices, whereas apical extrusion also requires downward contraction along the basolateral surfaces. To activate actin/myosin basolaterally, microtubules in neighboring cells reorient and target p115 RhoGEF to this site. Preventing microtubule reorientation restricts contraction to the apex, driving extrusion basally. Extrusion polarity has important implications for tumors where apoptosis is blocked but extrusion is not, as basal extrusion could enable these cells to initiate metastasis.
PMCID: PMC2742179  PMID: 19720875
9.  Xenopus Actin Depolymerizing Factor/Cofilin (XAC) Is Responsible for the Turnover of Actin Filaments in Listeria monocytogenes Tails 
The Journal of Cell Biology  1997;136(6):1323-1332.
In contrast to the slow rate of depolymerization of pure actin in vitro, populations of actin filaments in vivo turn over rapidly. Therefore, the rate of actin depolymerization must be accelerated by one or more factors in the cell. Since the actin dynamics in Listeria monocytogenes tails bear many similarities to those in the lamellipodia of moving cells, we have used Listeria as a model system to isolate factors required for regulating the rapid actin filament turnover involved in cell migration. Using a cell-free Xenopus egg extract system to reproduce the Listeria movement seen in a cell, we depleted candidate depolymerizing proteins and analyzed the effect that their removal had on the morphology of Listeria tails. Immunodepletion of Xenopus actin depolymerizing factor (ADF)/cofilin (XAC) from Xenopus egg extracts resulted in Listeria tails that were approximately five times longer than the tails from undepleted extracts. Depletion of XAC did not affect the tail assembly rate, suggesting that the increased tail length was caused by an inhibition of actin filament depolymerization. Immunodepletion of Xenopus gelsolin had no effect on either tail length or assembly rate. Addition of recombinant wild-type XAC or chick ADF protein to XAC-depleted extracts restored the tail length to that of control extracts, while addition of mutant ADF S3E that mimics the phosphorylated, inactive form of ADF did not reduce the tail length. Addition of excess wild-type XAC to Xenopus egg extracts reduced the length of Listeria tails to a limited extent. These observations show that XAC but not gelsolin is essential for depolymerizing actin filaments that rapidly turn over in Xenopus extracts. We also show that while the depolymerizing activities of XAC and Xenopus extract are effective at depolymerizing normal filaments containing ADP, they are unable to completely depolymerize actin filaments containing AMPPNP, a slowly hydrolyzible ATP analog. This observation suggests that the substrate for XAC is the ADP-bound subunit of actin and that the lifetime of a filament is controlled by its nucleotide content.
PMCID: PMC2132508  PMID: 9087446

Results 1-9 (9)