125 research outputs found
Expression of Foxm1 Transcription Factor in Cardiomyocytes Is Required for Myocardial Development
Forkhead Box M1 (Foxm1) is a transcription factor essential for organ morphogenesis and development of various cancers. Although complete deletion of Foxm1 in Foxm1β/β mice caused embryonic lethality due to severe abnormalities in multiple organ systems, requirements for Foxm1 in cardiomyocytes remain to be determined. This study was designed to elucidate the cardiomyocyte-autonomous role of Foxm1 signaling in heart development. We generated a new mouse model in which Foxm1 was specifically deleted from cardiomyocytes (Nkx2.5-Cre/Foxm1fl/f mice). Deletion of Foxm1 from cardiomyocytes was sufficient to disrupt heart morphogenesis and induce embryonic lethality in late gestation. Nkx2.5-Cre/Foxm1fl/fl hearts were dilated with thinning of the ventricular walls and interventricular septum, as well as disorganization of the myocardium which culminated in cardiac fibrosis and decreased capillary density. Cardiomyocyte proliferation was diminished in Nkx2.5-Cre/Foxm1fl/fl hearts owing to altered expression of multiple cell cycle regulatory genes, such as Cdc25B, Cyclin B1, Plk-1, nMyc and p21cip1. In addition, Foxm1 deficient hearts displayed reduced expression of CaMKIIΞ΄, Hey2 and myocardin, which are critical mediators of cardiac function and myocardial growth. Our results indicate that Foxm1 expression in cardiomyocytes is critical for proper heart development and required for cardiomyocyte proliferation and myocardial growth
ΠΡΠ΅ΠΊΡΠΈΠ²Π½ΡΡΡΡ Π΄ΠΎΡΠΎΡΡΠ²Π°Π½Π½Ρ Π³ΡΠ±ΡΠΈΠ΄Π½ΠΈΡ ΠΏΠΎΡΠΎΡΡΡ Π· ΡΡΠ·Π½ΠΎΡ ΠΌΠ°ΡΠΎΡ ΠΏΡΠΈ ΠΏΠΎΡΡΠ°Π½ΠΎΠ²ΡΡ Π·Π° ΡΡΠ΄ΠΊΠΎΡ ΡΠΈΡΡΠ΅ΠΌΠΈ ΡΡ Π³ΠΎΠ΄ΡΠ²Π»Ρ
The intensity of growth of piglets, their preservation during rearing, and the payment of feed by the increments of animals that were placed for rearing with a design live weight of 7 kg and 20 % less than the design weight β 5.5 kg were studied. Also, the ratio of consumption of compound feed of different recipes during rearing, their cost, and the efficiency of rearing piglets at different staged live weights were studied. It was established that piglets that weighed 1.58 kg less at the beginning of rearing, when placed on rearing during this period, showed 20.9 % lower growth energy, due to which they had 19.6 % lower absolute growth during this period, which caused together with a lower production weight, a 20.3 % lower weight when transferred to fattening and an 8.8 % worse feed payment in increments, they consumed 31.4 % more of the expensive first pre-starter feed during the growing period, and 11.9 % less than the second cheaper pre-starter compound feed and 42.6 % less than the cheapest starter compound feed, as a result of which the cost of feed consumed by the animals of the experimental group was 10.6 % lower compared to the analogs of the experimental group. But taking into account the significantly lower absolute growth of the animals of the experimental group, the cost of feed for 1 kg of growth was 11.2 % higher in comparison with the similar indicator of animals that were put on growing at a designed live weight of 7.0 kg. At the same time, rearing piglets under the conditions of putting them into this process with the design live weight contributed to a decrease of 11.2 % in the cost of feed per kilogram of growth, an increase of 20.3 % in the cost of one piglet after the completion of rearing, and a 23.1 % increase in the income from its sale and 1.07 % higher profitability of raising one head, but resulted in 10.6 % higher feed and operating cost of rearing 1 head and 19.6 % higher operating cost of one piglet at the end of rearing.ΠΠΈΠ²ΡΠ°Π»ΠΈΡΡ ΡΠ½ΡΠ΅Π½ΡΠΈΠ²Π½ΡΡΡΡ ΡΠΎΡΡΡ ΠΏΠΎΡΠΎΡΡΡ, ΡΡ
Π·Π±Π΅ΡΠ΅ΠΆΠ΅Π½ΡΡΡΡ ΠΏΡΠ΄ ΡΠ°Ρ Π΄ΠΎΡΠΎΡΡΠ²Π°Π½Π½Ρ ΡΠ° ΠΎΠΏΠ»Π°ΡΠ° ΠΊΠΎΡΠΌΡ ΠΏΡΠΈΡΠΎΡΡΠ°ΠΌΠΈ ΡΠ²Π°ΡΠΈΠ½, ΡΠΊΡ Π±ΡΠ»ΠΈ ΠΏΠΎΡΡΠ°Π²Π»Π΅Π½Ρ Π½Π° Π΄ΠΎΡΠΎΡΡΠ²Π°Π½Π½Ρ Π·Π° ΠΏΡΠΎΠ΅ΠΊΡΠ½ΠΎΡ ΠΆΠΈΠ²ΠΎΡ ΠΌΠ°ΡΠΈ 7 ΠΊΠ³ ΡΠ° Π½Π° 20 % ΠΌΠ΅Π½ΡΠΎΡ Π²ΡΠ΄ ΠΏΡΠΎΠ΅ΠΊΡΠ½ΠΎΡ β 5,5 ΠΊΠ³. Π’Π°ΠΊΠΎΠΆ Π²ΠΈΠ²ΡΠ°Π»ΠΎΡΡ ΡΠΏΡΠ²ΡΠ΄Π½ΠΎΡΠ΅Π½Π½Ρ ΡΠΏΠΎΠΆΠΈΠ²Π°Π½Π½Ρ ΠΊΠΎΠΌΠ±ΡΠΊΠΎΡΠΌΡΠ² ΡΡΠ·Π½ΠΈΡ
ΡΠ΅ΡΠ΅ΠΏΡΡΡ ΠΏΡΠ΄ ΡΠ°Ρ Π΄ΠΎΡΠΎΡΡΠ²Π°Π½Π½Ρ, ΡΡ
Π½Ρ Π²Π°ΡΡΡΡΡΡ ΡΠ° Π΅ΡΠ΅ΠΊΡΠΈΠ²Π½ΡΡΡΡ Π΄ΠΎΡΠΎΡΡΠ²Π°Π½Π½Ρ ΠΏΠΎΡΠΎΡΡΡ Π·Π° ΡΡΠ·Π½ΠΎΡ ΠΏΠΎΡΡΠ°Π½ΠΎΠ²ΠΎΡΠ½ΠΎΡ ΠΆΠΈΠ²ΠΎΡ ΠΌΠ°ΡΠΈ. ΠΡΡΠ°Π½ΠΎΠ²Π»Π΅Π½Π½ΠΎ, ΡΠΎ ΠΏΠΎΡΠΎΡΡΡΠ°, ΡΠΊΡ ΠΌΠ°Π»ΠΈ Π½Π° ΠΏΠΎΡΠ°ΡΠΎΠΊ Π΄ΠΎΡΠΎΡΡΠ²Π°Π½Π½Ρ ΠΌΠ΅Π½ΡΡ Π½Π° 1,58 ΠΊΠ³ Π²Π°Π³Ρ, ΠΏΡΠΈ ΠΏΠΎΡΡΠ°Π½ΠΎΠ²ΡΡ Π½Π° Π΄ΠΎΡΠΎΡΡΠ²Π°Π½Π½Ρ ΠΏΡΠ΄ ΡΠ°Ρ ΡΡΠΎΠ³ΠΎ ΠΏΠ΅ΡΡΠΎΠ΄Ρ Π²ΠΈΡΠ²ΠΈΠ»ΠΈ Π½Π° 20,9 % Π½ΠΈΠΆΡΡ Π΅Π½Π΅ΡΠ³ΡΡ ΡΠΎΡΡΡ, Π·Π° ΡΠ°Ρ
ΡΠ½ΠΎΠΊ ΡΠΎΠ³ΠΎ ΠΌΠ°Π»ΠΈ ΠΌΠ΅Π½ΡΡ Π½Π° 19,6 % Π°Π±ΡΠΎΠ»ΡΡΠ½Ρ ΠΏΡΠΈΡΠΎΡΡΠΈ Π·Π° ΡΠ΅ΠΉ ΠΏΠ΅ΡΡΠΎΠ΄, ΡΠΎ ΡΠΏΡΠΈΡΠΈΠ½ΠΈΠ»ΠΎ ΡΠ°Π·ΠΎΠΌ Π· ΠΌΠ΅Π½ΡΠΎΡ ΠΏΠΎΡΡΠ°Π½ΠΎΠ²ΠΎΡΠ½ΠΎΡ ΠΌΠ°ΡΠΎΡ Π½Π° 20,3 % Π½ΠΈΠΆΡΡ ΠΌΠ°ΡΡ ΠΏΡΠΈ ΠΏΠ΅ΡΠ΅Π²Π΅Π΄Π΅Π½Π½Ρ Π½Π° Π²ΡΠ΄Π³ΠΎΠ΄ΡΠ²Π»Ρ ΡΠ° Π³ΡΡΡΡ Π½Π° 8,8 % ΠΎΠΏΠ»Π°ΡΡ ΠΊΠΎΡΠΌΡ ΠΏΡΠΈΡΠΎΡΡΠ°ΠΌΠΈ, Π²ΠΎΠ½ΠΈ ΡΠΏΠΎΠΆΠΈΠ»ΠΈ Π·Π° ΡΠ°Ρ Π΄ΠΎΡΠΎΡΡΠ²Π°Π½Π½Ρ Π½Π° 31,4 % Π±ΡΠ»ΡΡΠ΅ Π΄ΠΎΡΠΎΠ³ΠΎΠ³ΠΎ ΠΏΠ΅ΡΡΠΎΠ³ΠΎ ΠΏΡΠ΅ΡΡΠ°ΡΡΠ΅ΡΠ½ΠΎΠ³ΠΎ ΠΊΠΎΡΠΌΡ, ΡΠ° Π½Π° 11,9% ΠΌΠ΅Π½ΡΠ΅ Π΄Π΅ΡΠ΅Π²ΡΠΎΠ³ΠΎ Π΄ΡΡΠ³ΠΎΠ³ΠΎ ΠΏΡΠ΅ΡΡΠ°ΡΡΠ΅ΡΠ½ΠΎΠ³ΠΎ ΠΊΠΎΠΌΠ±ΡΠΊΠΎΡΠΌΡ Ρ Π½Π° 42,6% ΠΌΠ΅Π½ΡΠ΅ Π½Π°ΠΉΠ±ΡΠ»ΡΡ Π΄Π΅ ΡΠ΅Π²ΡΠΎΠ³ΠΎ ΡΡΠ°ΡΡΠ΅ΡΠ½ΠΎΠ³ΠΎ ΠΊΠΎΠΌΠ±ΡΠΊΠΎΡΠΌΡ, Π² ΡΠ΅Π·ΡΠ»ΡΡΠ°ΡΡ ΡΠΎΠ³ΠΎ Π²Π°ΡΡΡΡΡΡ ΡΠΏΠΎΠΆΠΈΡΠΈΡ
ΠΊΠΎΡΠΌΡΠ² ΡΠ²Π°ΡΠΈΠ½Π°ΠΌΠΈ Π΄ΠΎΡΠ»ΡΠ΄Π½ΠΎΡ Π³ΡΡΠΏΠΈ Π²ΠΈΡΠ²ΠΈΠ»ΠΎΡΡ Π½Π° 10,6 % ΠΌΠ΅Π½ΡΠΎΡ ΠΏΠΎΡΡΠ²Π½ΡΠ½ΠΎ Π· Π°Π½Π°Π»ΠΎΠ³Π°ΠΌΠΈ Π΄ΠΎΡΠ»ΡΠ΄Π½ΠΎΡ Π³ΡΡΠΏΠΈ. ΠΠ»Π΅ Π²ΡΠ°Ρ
ΠΎΠ²ΡΡΡΠΈ ΡΡΡΡΡΠ²ΠΎ Π½ΠΈΠΆΡΠΈΠΉ Π°Π±ΡΠΎΠ»ΡΡΠ½ΠΈΠΉ ΠΏΡΠΈΡΡΡΡ Ρ ΡΠ²Π°ΡΠΈΠ½ Π΄ΠΎΡΠ»ΡΠ΄Π½ΠΎΡ Π³ΡΡΠΏΠΈ, ΠΊΠΎΡΠΌΠΎΠ²Π° ΡΠΎΠ±ΡΠ²Π°ΡΡΡΡΡΡ 1 ΠΊΠ³ ΠΏΡΠΈΡΠΎΡΡΡ Ρ Π½ΠΈΡ
Π²ΠΈΡΠ²ΠΈΠ»Π°ΡΡ Π½Π° 11,2 % Π²ΠΈΡΠΎΡ ΠΏΠΎΡΡΠ²Π½ΡΠ½ΠΎ Π· Π°Π½Π°Π»ΠΎΠ³ΡΡΠ½ΠΈΠΌ ΠΏΠΎΠΊΠ°Π·Π½ΠΈΠΊΠΎΠΌ ΡΠ²Π°ΡΠΈΠ½, ΡΠΊΠΈΡ
ΡΡΠ°Π²ΠΈΠ»ΠΈ Π½Π° Π΄ΠΎΡΠΎΡΡΠ²Π°Π½Π½Ρ Π·Π° ΠΏΡΠΎΠ΅ΠΊΡΠ½ΠΎΡ ΠΆΠΈΠ²ΠΎΡ ΠΌΠ°ΡΠΈ 7,0 ΠΊΠ³. ΠΠΎΠ΄Π½ΠΎΡΠ°Ρ Π΄ΠΎΡΠΎΡΡΠ²Π°Π½Π½Ρ ΠΏΠΎΡΡΡΡ Π·Π° ΡΠΌΠΎΠ² ΠΏΠΎΡΡΠ°Π½ΠΎΠ²ΠΊΠΈ ΡΡ
Π½Π° ΡΠ΅ΠΉ ΠΏΡΠΎΡΠ΅Ρ Π· ΠΏΡΠΎΠ΅ΠΊΡΠ½ΠΎΡ ΠΆΠΈΠ²ΠΎΡ ΠΌΠ°ΡΠΎΡ ΠΏΠΎΡΠΏΡΠΈΡΠ»ΠΎ Π·ΠΌΠ΅Π½ΡΠ΅Π½Π½Ρ Π½Π° 11,2 % ΠΊΠΎΡΠΌΠΎΠ²ΠΎΡ ΡΠΎΠ±ΡΠ²Π°ΡΡΠΎΡΡΡ ΠΎΠ΄Π½ΠΎΠ³ΠΎ ΠΊΡΠ»ΠΎΠ³ΡΠ°ΠΌΠ° ΠΏΡΠΈΡΠΎΡΡΡ, ΠΏΡΠ΄Π²ΠΈΡΠ΅Π½Π½Ρ Π½Π° 20,3 % Π²Π°ΡΡΠΎΡΡΡ ΠΎΠ΄Π½ΠΎΠ³ΠΎ ΠΏΠΎΡΠΎΡΡΡΠΈ ΠΏΠΎ Π·Π°Π²Π΅ΡΡΠ΅Π½Π½Ρ Π΄ΠΎΡΠΎΡΡΠ²Π°Π½Π½Ρ ΡΠ° Π½Π° 23,1 % Π΄ΠΎΡ
ΠΎΠ΄Ρ Π²ΡΠ΄ ΠΉΠΎΠ³ΠΎ ΡΠ΅Π°Π»ΡΠ·Π°ΡΡΡ Ρ Π½Π° 1,07 % Π²ΠΈΡΡΠΉ ΡΠ΅Π½ΡΠ°Π±Π΅Π»ΡΠ½ΠΎΡΡΡ Π²ΠΈΡΠΎΡΡΠ²Π°Π½Π½Ρ ΠΎΠ΄Π½ΡΡΡ Π³ΠΎΠ»ΠΎΠ²ΠΈ, Π°Π»Π΅ ΡΠΏΡΠΈΡΠΈΠ½ΠΈΠ»ΠΎ Π²ΠΈΡΡ Π½Π° 10,6 % ΠΊΠΎΡΠΌΠΎΠ²Ρ ΡΠ° ΠΎΠΏΠ΅ΡΠ°ΡΡΠΉΠ½Ρ ΡΠΎΠ±ΡΠ²Π°ΡΡΡΡΡΡ Π΄ΠΎΡΠΎΡΡΠ²Π°Π½Π½Ρ 1 Π³ΠΎΠ»ΠΎΠ²ΠΈ ΡΠ° Π½Π° 19,6 % ΠΎΠΏΠ΅ΡΠ°ΡΡΠΉΠ½Ρ ΡΠΎΠ±ΡΠ²Π°ΡΡΡΡΡΡ ΠΎΠ΄Π½ΠΎΠ³ΠΎ ΠΏΡΠ΄ΡΠ²ΠΈΠ½ΠΊΠ° Π½Π° ΠΊΡΠ½Π΅ΡΡ Π΄ΠΎΡΠΎΡΡΠ²Π°Π½Π½Ρ
Digital receivers for low-frequency radio telescopes UTR-2, URAN, GURT
This paper describes digital radio astronomical receivers used for decameter
and meter wavelength observations. This paper describes digital radio
astronomical receivers used for decameter and meter wavelength observations.
Since 1998, digital receivers performing on-the-fly dynamic spectrum
calculations or waveform data recording without data loss have been used at the
UTR-2 radio telescope, the URAN VLBI system, and the GURT new generation radio
telescope. Here we detail these receivers developed for operation in the strong
interference environment that prevails in the decameter wavelength range. Data
collected with these receivers allowed us to discover numerous radio
astronomical objects and phenomena at low frequencies, a summary of which is
also presented.Comment: 24 pages, 15 figure
FoxM1 Is a General Target for Proteasome Inhibitors
Proteasome inhibitors are currently in the clinic or in clinical trials, but the mechanism of their anticancer activity is not completely understood. The oncogenic transcription factor FoxM1 is one of the most overexpressed genes in human tumors, while its expression is usually halted in normal non-proliferating cells. Previously, we established that thiazole antibiotics Siomycin A and thiostrepton inhibit FoxM1 and induce apoptosis in human cancer cells. Here, we report that Siomycin A and thiostrepton stabilize the expression of a variety of proteins, such as p21, Mcl-1, p53 and hdm-2 and also act as proteasome inhibitors in vitro. More importantly, we also found that well-known proteasome inhibitors such as MG115, MG132 and bortezomib inhibit FoxM1 transcriptional activity and FoxM1 expression. In addition, overexpression of FoxM1 specifically protects against bortezomib-, but not doxorubicin-induced apoptosis. These data suggest that negative regulation of FoxM1 by proteasome inhibitors is a general feature of these drugs and it may contribute to their anticancer properties
Deletion of Forkhead Box M1 Transcription Factor from Respiratory Epithelial Cells Inhibits Pulmonary Tumorigenesis
The Forkhead Box m1 (Foxm1) protein is induced in a majority of human non-small cell lung cancers and its expression is associated with poor prognosis. However, specific requirements for the Foxm1 in each cell type of the cancer lesion remain unknown. The present study provides the first genetic evidence that the Foxm1 expression in respiratory epithelial cells is essential for lung tumorigenesis. Using transgenic mice, we demonstrated that conditional deletion of Foxm1 from lung epithelial cells (epFoxm1β/β mice) prior to tumor initiation caused a striking reduction in the number and size of lung tumors, induced by either urethane or 3-methylcholanthrene (MCA)/butylated hydroxytoluene (BHT). Decreased lung tumorigenesis in epFoxm1β/β mice was associated with diminished proliferation of tumor cells and reduced expression of Topoisomerase-2Ξ± (TOPO-2Ξ±), a critical regulator of tumor cell proliferation. Depletion of Foxm1 mRNA in cultured lung adenocarcinoma cells significantly decreased TOPO-2Ξ± mRNA and protein levels. Moreover, Foxm1 directly bound to and induced transcription of the mouse TOPO-2Ξ± promoter region, indicating that TOPO-2Ξ± is a direct target of Foxm1 in lung tumor cells. Finally, we demonstrated that a conditional deletion of Foxm1 in pre-existing lung tumors dramatically reduced tumor growth in the lung. Expression of Foxm1 in respiratory epithelial cells is critical for lung cancer formation and TOPO-2Ξ± expression in vivo, suggesting that Foxm1 is a promising target for anti-tumor therapy
CXCL12 and [N33A]CXCL12 in 5637 and HeLa Cells: Regulating HER1 Phosphorylation via Calmodulin/Calcineurin
In the human neoplastic cell lines 5637 and HeLa, recombinant CXCL12 elicited, as expected, downstream signals via both G-protein-dependent and Ξ²-arrestin-dependent pathways responsible for inducing a rapid and a late wave, respectively, of ERK1/2 phosphorylation. In contrast, the structural variant [N33A]CXCL12 triggered no Ξ²-arrestin-dependent phosphorylation of ERK1/2, and signaled via G protein-dependent pathways alone. Both CXCL12 and [N33A]CXCL12, however, generated signals that transinhibited HER1 phosphorylation via intracellular pathways. 1) Prestimulation of CXCR4/HER1-positive 5637 or HeLa cells with CXCL12 modified the HB-EGF-dependent activation of HER1 by delaying the peak phosphorylation of tyrosine 1068 or 1173. 2) Prestimulation with the synthetic variant [N33A]CXCL12, while preserving CXCR4-related chemotaxis and CXCR4 internalization, abolished HER1 phosphorylation. 3) In cells knockdown of Ξ²-arrestin 2, CXCL12 induced a full inhibition of HER1 like [N33A]CXCL12 in non-silenced cells. 4) HER1 phosphorylation was restored as usual by inhibiting PCK, calmodulin or calcineurin, whereas the inhibition of CaMKII had no discernable effect. We conclude that both recombinant CXCL12 and its structural variant [N33A]CXCL12 may transinhibit HER1 via G-proteins/calmodulin/calcineurin, but [N33A]CXCL12 does not activate Ξ²-arrestin-dependent ERK1/2 phosphorylation and retains a stronger inhibitory effect. Therefore, we demonstrated that CXCL12 may influence the magnitude and the persistence of signaling downstream of HER1 in turn involved in the proliferative potential of numerous epithelial cancer. In addition, we recognized that [N33A]CXCL12 activates preferentially G-protein-dependent pathways and is an inhibitor of HER1
Temporal Dissection of K-rasG12D Mutant In Vitro and In Vivo Using a Regulatable K-rasG12D Mouse Allele
Animal models which allow the temporal regulation of gene activities are valuable for dissecting gene function in tumorigenesis. Here we have constructed a conditional inducible estrogen receptor-K-rasG12D (ER-K-rasG12D) knock-in mice allele that allows us to temporally switch on or off the activity of K-ras oncogenic mutant through tamoxifen administration. In vitro studies using mice embryonic fibroblast (MEF) showed that a dose of tamoxifen at 0.05 Β΅M works optimally for activation of ER-K-rasG12D independent of the gender status. Furthermore, tamoxifen-inducible activation of K-rasG12D promotes cell proliferation, anchor-independent growth, transformation as well as invasion, potentially via activation of downstream MAPK pathway and cell cycle progression. Continuous activation of K-rasG12D in vivo by tamoxifen treatment is sufficient to drive the neoplastic transformation of normal lung epithelial cells in mice. Tamoxifen withdrawal after the tumor formation results in apoptosis and tumor regression in mouse lungs. Taken together, these data have convincingly demonstrated that K-ras mutant is essential for neoplastic transformation and this animal model may provide an ideal platform for further detailed characterization of the role of K-ras oncogenic mutant during different stages of lung tumorigenesis
Local Microenvironment Provides Important Cues for Cell Differentiation in Lingual Epithelia
Transgenic Keratin14-rtTA-PTR mice specifically express Keratin14 (K14) in the tongue epithelia, as well as co-express EGFP and the dominant negative ΞTgfbr2 genes upon treatment with Doxycycline (Dox). As TGF-Ξ² signaling negatively regulates the stem cell cycle and proliferation, its disruption by Dox induction in these transgenic mice shortens the cell cycle and allows observation of the final fate of those mutated cell lineages within a short period of time. Here, we used inducible transgenic mice to track the K14+ cells through the cell migration stream by immunohistochemical an immunofluorescent imaging. We showed that these cells have different development patterns from the tip to posterior of the tongue, achieved presumably by integrating positional information from the microenvironment. The expression of the K14 gene was variable, depending on the location of the tongue and papillae. Disruption of TGF-Ξ² signaling in K14+ progenitor cells resulted in proliferation of stem cell pools
Blimp1 Activation by AP-1 in Human Lung Cancer Cells Promotes a Migratory Phenotype and Is Inhibited by the Lysyl Oxidase Propeptide
B lymphocyte-induced maturation protein 1 (Blimp1) is a master regulator of B cell differentiation, and controls migration of primordial germ cells. Recently we observed aberrant Blimp1 expression in breast cancer cells resulting from an NF-ΞΊB RelB to Ras signaling pathway. In order to address the question of whether the unexpected expression of Blimp1 is seen in other epithelial-derived tumors, we selected lung cancers as they are frequently driven by Ras signaling. Blimp1 was detected in all five lung cancer cell lines examined and shown to promote lung cancer cell migration and invasion. Interrogation of microarray datasets demonstrated elevated BLIMP1 RNA expression in lung adenocarcinoma, pancreatic ductal carcinomas, head and neck tumors as well as in glioblastomas. Involvement of Ras and its downstream kinase c-Raf was confirmed using mutant and siRNA strategies. We next addressed the issue of mechanism of Blimp1 activation in lung cancer. Using knockdown and ectopic expression, the role of the Activator Protein (AP)-1 family of transcription factors was demonstrated. Further, chromatin immunoprecipitation assays confirmed binding to identified AP-1 elements in the BLIMP1 promoter of ectopically expressed c-Jun and of endogenous AP-1 subunits following serum stimulation. The propeptide domain of lysyl oxidase (LOX-PP) was identified as a tumor suppressor, with ability to reduce Ras signaling in lung cancer cells. LOX-PP reduced expression of Blimp1 by binding to c-Raf and inhibiting activation of AP-1, thereby attenuating the migratory phenotype of lung cancer cells. Thus, Blimp1 is a mediator of Ras/Raf/AP-1 signaling that promotes cell migration, and is repressed by LOX-PP in lung cancer
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