HOXA6: A Novel Candidate Gene in AML.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2312-2312
Author(s):  
Glenda J. McGonigle ◽  
Damian P.J. Finnegan ◽  
Mary Frances McMullin ◽  
Terence R.J. Lappin ◽  
Alexander Thompson
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Growth Factor ◽  
Candidate Gene ◽  
Cell Lines ◽  
S Phase ◽  
Response To Therapy ◽  
Pcr Analysis ◽  
A6 Cells ◽  
Cell Cycle Status

Abstract Molecular classification of acute myeloid leukemia (AML) has identified several candidate genes that could potentially define prognosis and response to therapy. One such candidate, identified from microarray studies, is the Class I homeobox gene HOXA9. The HOX gene network encodes master regulators of developmental processes including hemopoiesis. To quantify the contribution of this network of genes in AML, we carried out specific RQ-PCR analysis on twenty-four de novo patient samples using a subset of genes (12 HOX and MEIS1) selected on the basis of their recently reported expression in AML. HOXA6 was ranked, as the most highly expressed gene (range 1 x 103 – 2 x 107 copies per 50 ng RNA), substantially higher than HOXA9 (see Table). Further analysis identified high expression of HOXA6 in both human myeloid cell lines and CD34+ enriched primary progenitors. Parallel studies with murine progenitors (c-Kit+, Lin−) and cell lines also showed a preponderance of Hoxa6 expression over other family members including Hoxa9 and Hoxb4. Several hemopoietic cell lines, namely Ba/F3, EML, FDCP-Mix A4 and 32Dcl3 were subsequently used to investigate Hoxa6 regulation following differentiation or growth factor stimuli. Hoxa6 expression decreased with cell differentiation and growth factor depletion/replenishment studies indicated a cell-cycle component for Hoxa6 regulation. Direct evaluation of cell-cycle status, using Hoechst 33342 staining and cell sorting, identified peak expression of Hoxa6 during S-phase. Gene deletion studies involving Hox tend to result in either a moderate or no phenotype, presumably due to intrinsic compensatory mechanisms. We therefore overexpressed HOXA6 in the Ba/F3 cell line to gain functional insights. Ba/F3-A6 cells were compared to mock-transfected and vector controls on the basis of proliferation, maturation, cell-cycle status, growth factor-dependence and apoptosis. The Ba/F3-A6 cells displayed a growth advantage over normal cells in the presence of IL-3 and maturation was not impaired. Cell-cycle analysis showed a reduction in the number of cells in both G2M and S-phase, associated with accumulation in the pre G1-phase, indicative of increased apoptosis. IL-3 depletion studies of Ba/F3-A6 cells indicated substantial factor-independent growth compared to controls, implying oncogenic potential for HOXA6. In support of this, a recent report (Mamo et al, Blood. 2006 Jul 15;108(2):622–9) indicated Hoxa6 as a potential collaborator in a Meis1-induced model of AML. Taken together these findings identify Hoxa6 as a novel candidate gene in AML with the capacity to alter growth and survival of hemopoietic cells. Gene Expression Ranking of HOX and MEIS1 in AML. GENE EXPRESSION RANGE MEAN RANK S.D. OVERALL RANK Expression values (copies per 50 ng RNA) compiled from primary AML patient samples (n=24) or * (n=12). S.D = standard deviation. HOXA6 1.2 x 103 – 1.7 x 107 2.2 1.6 1 HOXB3 9.3 x 101 – 8.4 x 106 3.2 2.5 2 HOXB2* 7.9 x 102 – 5.4 x 106 3.4 2.0 3 HOXA9 4.0 x 101 – 5.3 x 106 5.3 2.4 4 MEIS1 0.6 x 101 – 8.4 x 106 5.4 2.7 5 HOXA10* 2.4 x 102 – 1.7 x 105 5.5 3.2 6 HOXB4 1.5 x 102 – 7.8 x 105 5.5 3.2 7 HOXA7* 5.3 x 103 – 1.8 x 106 5.7 1.7 8 HOXB6 2.3 x 101 – 8.8 x 105 6.6 2.8 9 HOXA4 4.1 x 101 – 1.1 x 105 7.9 3.4 10 HOXA5* 3.4 x 101 – 4.3 x 104 9.3 2.8 11 HOXC6 1.0 x 101 – 3.2 x 103 9.7 2.3 12 HOXA11* 4.0 x 101 – 6.1 x 103 10.6 2.2 13

scholarly journals Retinoblastoma 1 (RB1) modulates the proliferation of chicken preadipocytes

2018 ◽  
Author(s):  
Yu-Xiang Wang ◽  
Hai-Xia Wang ◽  
Wei Na ◽  
Fei-Yue Qin ◽  
Zhi-Wei Zhang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Phase Transition ◽  
Cell Cycle ◽  
Gene Expression Analysis ◽  
Mammalian Species ◽  
S Phase ◽  
Pcr Analysis ◽  
Quantitative Real Time Pcr ◽  
Ki 67

AbstractRetinoblastoma 1 (RB1) has been extensively studied in mammalian species, but its function in avian species is unclear. The objective of this study was to reveal the role of chicken RB1 (Gallus gallus RB1, gRB1) in the proliferation of preadipocytes. In the current study, quantitative real-time PCR analysis showed that the expression levels of gRB1 transiently increased during the proliferation of preadipocytes. The MTT assay showed that gRB1 overexpression suppressed preadipocyte proliferation, and gRB1 interference promoted preadipocyte proliferation. Additionally, cell-cycle analysis indicated that gRB1 may play a crucial role in the G1/S transition. Consistently, gene expression analysis showed that gRB1 knockdown promoted marker of proliferation Ki-67 (MKi67) expression at 96 h (P < 0.05), and that overexpression of gRB1 reduced MKi67 expression at 72 h (P < 0.05). Together, our study demonstrated that gRB1 inhibited preadipocyte proliferation at least in part by inhibiting the G1 to S phase transition.

scholarly journals Gene Expression Alterations Associated with Oleuropein-Induced Antiproliferative Effects and S-Phase Cell Cycle Arrest in Triple-Negative Breast Cancer Cells

Nutrients ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3755
Author(s):  
Samia S. Messeha ◽  
Najla O. Zarmouh ◽  
Abrar Asiri ◽  
Karam F. A. Soliman
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Cell Cycle ◽  
Cell Lines ◽  
Triple Negative ◽  
S Phase ◽  
Phase Cell ◽  
Tnf Receptor ◽  
Interacting Protein ◽  
Cycle Arrest

It is known that the Mediterranean diet is effective in reducing the risk of several chronic diseases, including cancer. A critical component of the Mediterranean diet is olive oil, and the relationship between olive oil consumption and the reduced risk of cancer has been established. Oleuropein (OL) is the most prominent polyphenol component of olive fruits and leaves. This compound has been shown to have potent properties in various types of cancers, including breast cancer. In the present study, the molecular mechanism of OL was examined in two racially different triple-negative breast cancer (TNBC) cell lines—African American (AA, MDA-MB-468) and Caucasian American (CA, MDA-MB-231). The data obtained showed that OL effectively inhibits cell growth in both cell lines, concomitant with S-phase cell cycle arrest-mediated apoptosis. The results also showed that OL-treated MDA-MB-468 cells were two-fold more sensitive to OL antiproliferative effect than MDA-MB-231 cells were. At lower concentrations, OL modified the expression of many apoptosis-involved genes. OL was more effective in MDA-MB-468, compared to MDA-MB-231 cells, in terms of the number and the fold-change of the altered genes. In MDA-MB-468 cells, OL induced a noticeable transcription activation in fourteen genes, including two members of the caspase family: caspase 1 (CASP1) and caspase 14 (CASP14); two members of the TNF receptor superfamily: Fas-associated via death domain (FADD) and TNF receptor superfamily 21 (TNFRSF21); six other proapoptotic genes: growth arrest and DNA damage-inducible 45 alpha (GADD45A), cytochrome c somatic (CYCS), BCL-2 interacting protein 2 (BNIP2), BCL-2 interacting protein 3 (BNIP3), BH3 interacting domain death agonist (BID), and B-cell lymphoma/leukemia 10 (BCL10); and the CASP8 and FADD-like apoptosis regulator (CFLAR) gene. Moreover, in MDA-MB-468 cells, OL induced a significant upregulation in two antiapoptotic genes: bifunctional apoptosis regulator (BFAR) and B-Raf proto-oncogene (BRAF) and a baculoviral inhibitor of apoptosis (IAP) repeat-containing 3 (BIRC3). On the contrary, in MDA-MB-231 cells, OL showed mixed impacts on gene expression. OL significantly upregulated the mRNA expression of four genes: BIRC3, receptor-interacting serine/threonine kinase 2 (RIPK2), TNF receptor superfamily 10A (TNFRSF10A), and caspase 4 (CASP4). Additionally, another four genes were repressed, including caspase 6 (CASP6), pyrin domain (PYD), and caspase recruitment domain (CARD)-containing (PAYCARD), baculoviral IAP repeat-containing 5 (BIRC5), and the most downregulated TNF receptor superfamily member 11B (TNFRSF11B, 16.34-fold). In conclusion, the data obtained indicate that the two cell lines were markedly different in the anticancer effect and mechanisms of oleuropein’s ability to alter apoptosis-related gene expressions. The results obtained from this study should also guide the potential utilization of oleuropein as an adjunct therapy for TNBC to increase chemotherapy effectiveness and prevent cancer progression.

scholarly journals Erythropoietin-specific cell cycle progression in erythroid subclones of the interleukin-3-dependent cell line 32D [published erratum appears in Blood 1993 Jun 1;81(11):3168]

Blood ◽  
1993 ◽  
Vol 81 (4) ◽  
pp. 935-941 ◽  
Author(s):  
Y Shimada ◽  
G Migliaccio ◽  
H Ralph ◽  
AR Migliaccio ◽  
H] Shaw H$[corrected to Ralph
Keyword(s):  
Cell Cycle ◽  
Growth Factors ◽  
Growth Factor ◽  
Cell Lines ◽  
Suicide Rate ◽  
S Phase ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Dependent Cell ◽  
Stimulating Factor

Recently, a variety of growth factor-dependent subclones of the murine interleukin-3 (IL-3)-dependent cell line 32D have been isolated. These subclones include those dependent for growth on erythropoietin (Epo) (32D Epo), granulocyte-macrophage colony-stimulating factor (GM-CSF) (32D GM), or granulocyte colony-stimulating factor (G-CSF) (32D G). 32D Epo1.1 is a revertant of 32D Epo and is capable of growing in IL-3. These cell lines express the differentiation program appropriate to the specific growth factor and depend on the growth factors not only for proliferation but also for survival. To determine how the signal for proliferation is triggered by various growth factors, we examined the DNA histograms and the expression of cell cycle-specific genes in the different cell lines. The cell cycle-specific genes analyzed were myc (early G1), myb (late G1), and the structural genes for the calcium- binding protein 2A9 (middle G1) and histone H3 (G1-S boundary). The DNA histogram analysis of cells in the logarithmic phase of growth showed that approximately 40% of 32D, 32D GM, 32D G, and 32D Epo1.1 (growing in IL-3) were cells with a 2N DNA content (and therefore in G0/G1), and another 40% have a DNA content intermediate between 2N and 4N (in S phase). In contrast, 32D Epo and 32D Epo1.1 (growing in Epo) had fewer cells in the G0/G1 phase of the cell cycle compared with the number of cells that were in the S phase (19% to 31% v 69% to 78%, respectively). Because all the cell lines have comparable doubling times (15 to 18 hours), the cell distribution among the phases of the cell cycle is proportional to the length of the phase. Therefore, cells growing in IL- 3 (32D and 32D Epo1.1), GM-CSF (32D GM), or G-CSF (32D G) progress along the cycle in a manner typical of previously reported nontransformed cell lines. In contrast, cells growing in Epo (32D Epo or 32D Epo1.1) spend relatively less time in G0/G1 and correspondingly more time in S. These data were confirmed by the analysis of the tritiated thymidine (3H-TdR) suicide rate and of the expression of cell cycle-specific genes. The 32D and 32D Epo1.1 cells growing in IL-3 had a suicide rate of congruent to 50%, whereas the suicide rate of 32D Epo and 32D Epo1.1 growing in Epo was higher than 75%.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Erythropoietin-specific cell cycle progression in erythroid subclones of the interleukin-3-dependent cell line 32D [published erratum appears in Blood 1993 Jun 1;81(11):3168]

Blood ◽  
1993 ◽  
Vol 81 (4) ◽  
pp. 935-941 ◽  
Author(s):  
Y Shimada ◽  
G Migliaccio ◽  
H Ralph ◽  
AR Migliaccio ◽  
H] Shaw H$[corrected to Ralph
Keyword(s):  
Cell Cycle ◽  
Growth Factors ◽  
Growth Factor ◽  
Cell Lines ◽  
Suicide Rate ◽  
S Phase ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Dependent Cell ◽  
Stimulating Factor

Abstract Recently, a variety of growth factor-dependent subclones of the murine interleukin-3 (IL-3)-dependent cell line 32D have been isolated. These subclones include those dependent for growth on erythropoietin (Epo) (32D Epo), granulocyte-macrophage colony-stimulating factor (GM-CSF) (32D GM), or granulocyte colony-stimulating factor (G-CSF) (32D G). 32D Epo1.1 is a revertant of 32D Epo and is capable of growing in IL-3. These cell lines express the differentiation program appropriate to the specific growth factor and depend on the growth factors not only for proliferation but also for survival. To determine how the signal for proliferation is triggered by various growth factors, we examined the DNA histograms and the expression of cell cycle-specific genes in the different cell lines. The cell cycle-specific genes analyzed were myc (early G1), myb (late G1), and the structural genes for the calcium- binding protein 2A9 (middle G1) and histone H3 (G1-S boundary). The DNA histogram analysis of cells in the logarithmic phase of growth showed that approximately 40% of 32D, 32D GM, 32D G, and 32D Epo1.1 (growing in IL-3) were cells with a 2N DNA content (and therefore in G0/G1), and another 40% have a DNA content intermediate between 2N and 4N (in S phase). In contrast, 32D Epo and 32D Epo1.1 (growing in Epo) had fewer cells in the G0/G1 phase of the cell cycle compared with the number of cells that were in the S phase (19% to 31% v 69% to 78%, respectively). Because all the cell lines have comparable doubling times (15 to 18 hours), the cell distribution among the phases of the cell cycle is proportional to the length of the phase. Therefore, cells growing in IL- 3 (32D and 32D Epo1.1), GM-CSF (32D GM), or G-CSF (32D G) progress along the cycle in a manner typical of previously reported nontransformed cell lines. In contrast, cells growing in Epo (32D Epo or 32D Epo1.1) spend relatively less time in G0/G1 and correspondingly more time in S. These data were confirmed by the analysis of the tritiated thymidine (3H-TdR) suicide rate and of the expression of cell cycle-specific genes. The 32D and 32D Epo1.1 cells growing in IL-3 had a suicide rate of congruent to 50%, whereas the suicide rate of 32D Epo and 32D Epo1.1 growing in Epo was higher than 75%.(ABSTRACT TRUNCATED AT 400 WORDS)

ANKHD1 Silencing Induces S-Phase Arrest and Modulates Cell Cycle Gene Expression in Human Myeloma Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1828-1828
Author(s):  
Anamika Dhyani ◽  
Adriana S S Duarte ◽  
Patricia Favaro ◽  
Sara T Olalla Saad
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Multiple Myeloma ◽  
Cell Lines ◽  
Lentiviral Vector ◽  
Myeloma Cell ◽  
S Phase ◽  
Cell Cycle Gene ◽  
Myeloma Cells ◽  
Protein Levels

Abstract Abstract 1828 ANKHD1 is a multiple ankyrin repeats containing protein with a single KH domain. It is a large protein (∼ 280 kDa) derived from an 8 kb transcript. The ANKHD1 gene, present in human chromosome 5q31.3 as a single copy is ubiquitously expressed in normal human tissues and reported to be highly expressed in cancers, such as acute leukemia. Previous study showed higher expression of ANKHD1 in bone marrow plasma cells (CD138+) from Multiple Myeloma patients as compared to control (1) and it is also over expressed in multiple myeloma cell lines such as MM1S, MM1R, U266 and RPMI 8266 at both mRNA and protein level (2). However, the functional role of ANKHD1 in myeloma cells is unknown. In the present study, by silencing ANKHD1 gene expression in glucocorticoid resistant (U266) and sensitive (MM1S) myeloma cell lines, we studied its effect on cell cycle, proliferation and apoptosis. For gene silencing, specific shRNA-expressing lentiviral vector targeting the ANKHD1 gene and as negative control, sequence specific to Lac z gene were used. Cell growth was measured using the MTT colorimetric assay, whereas for apoptosis and cell cycle analysis Flow cytometry was used. Western blot and RTPCR were used for studying gene expression and protein levels, respectively. The results showed that lentiviral vector containing coding sequences for shRNA significantly downregulated ANKHD1 gene expression in Multiple Myeloma cells at the mRNA and the protein levels (p<0.05). Furthermore, we found that the cell cycle was arrested at S phase and the cell proliferation was significantly inhibited in both cell lines studied (p<0.05). However, ANKHD1 suppression did not induce apoptosis in myeloma cells, as evidenced by annexin V binding assay and flow cytometric detection of sub-G1 DNA content. To address the mechanism of the antiproliferative effect of ANKHD1 silencing, we examined the effect of ANKHD1 inhibition on cell cycle-related gene expression and proteins. ANKHD1 suppression caused downregulation of CDKN1B (p27), CCNB1 (cyclin B1), CDC25, CCNE1 (cyclin E1) and WEE 1 gene expression. There was no significant change in CCNA2 (Cyclin A2), CDC20 expression at mRNA levels. On the other hand, expression of CDKN1A (p21),which inhibits cyclin dependent kinases (CDKs) and plays role in preventing proliferation, was highly upregulated in both the cell lines. At protein levels, expression of Cdk2,Cdk4, p27 (CDKN1B) and E2F1 was decreased in both the cell lines with almost complete inhibition of expression in U266 cells. Taken together, the above results suggest that accumulation of cells in S phase (S phase arrest) can be due to inhibition of CDKs which binds with cyclins and are responsible for progression of cell cycle. Further, this inhibition of CDKs could be associated to increased induction of (CDKN1A) p21 in both cell lines. In conclusion, the present study demonstrates that the suppression of ANKHD1 potently inhibits proliferation and promotes cell cycle arrest without affecting rate of apoptosis in both glucocorticoid resistant as well as sensitive multiple myeloma cells. Also, as ANKHD1 suppression prevents S to G2/M progression, ANKHD1 protein might have role in cell cycle control by modulating cell cycle gene expression in intra S phase check point. The mechanisms modulating expression of these genes are under investigation. Further studies with combination of drugs that induce apoptosis and suppression of ANKHD1 may be an effective strategy for treatment of cancers, and therefore needed to be explored. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Doxorubicin treatment modulates chemoresistance and affects the cell cycle in two canine mammary tumour cell lines

2021 ◽  
Vol 17 (1) ◽  
Author(s):  
Michela Levi ◽  
Roberta Salaroli ◽  
Federico Parenti ◽  
Raffaella De Maria ◽  
Augusta Zannoni ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Lines ◽  
Tumour Cell ◽  
S Phase ◽  
Mammary Tumour ◽  
Cancer Resistance ◽  
Neoplastic Cells ◽  
Canine Mammary Tumour ◽  
Tumour Cell Lines

Abstract Background Doxorubicin (DOX) is widely used in both human and veterinary oncology although the onset of multidrug resistance (MDR) in neoplastic cells often leads to chemotherapy failure. Better understanding of the cellular mechanisms that circumvent chemotherapy efficacy is paramount. The aim of this study was to investigate the response of two canine mammary tumour cell lines, CIPp from a primary tumour and CIPm, from its lymph node metastasis, to exposure to EC50(20h) DOX at 12, 24 and 48 h of treatment. We assessed the uptake and subcellular distribution of DOX, the expression and function of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP), two important MDR mediators. To better understand this phenomenon the effects of DOX on the cell cycle and Ki67 cell proliferation index and the expression of p53 and telomerase reverse transcriptase (TERT) were also evaluated by immunocytochemistry (ICC). Results Both cell lines were able to uptake DOX within the nucleus at 3 h treatment while at 48 h DOX was absent from the intracellular compartment (assessed by fluorescence microscope) in all the surviving cells. CIPm, originated from the metastatic tumour, were more efficient in extruding P-gp substrates. By ICC and qRT-PCR an overall increase in both P-gp and BCRP were observed at 48 h of EC50(20h) DOX treatment in both cell lines and were associated with a striking increase in the percentage of p53 and TERT expressing cells by ICC. The cell proliferation fraction was decreased at 48 h in both cell lines and cell cycle analysis showed a DOX-induced arrest in the S phase for CIPp, while CIPm had an increase in cellular death without arrest. Both cells lines were therefore composed by a fraction of cells sensible to DOX that underwent apoptosis/necrosis. Conclusions DOX administration results in interlinked modifications in the cellular population including a substantial effect on the cell cycle, in particular arrest in the S phase for CIPp and the selection of a subpopulation of neoplastic cells bearing MDR phenotype characterized by P-gp and BCRP expression, TERT activation, p53 accumulation and decrease in the proliferating fraction. Important information is given for understanding the dynamic and mechanisms of the onset of drug resistance in a neoplastic cell population.

Growth factor-deprived BALB/c 3T3 murine fibroblasts can enter the S phase after induction of c-myc gene expression

1987 ◽  
Vol 7 (10) ◽  
pp. 3554-3560
Author(s):  
F Cavalieri ◽  
M Goldfarb
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Dna Synthesis ◽  
S Phase ◽  
3T3 Cells ◽  
Glucocorticoid Treatment ◽  
Plasmid Construct ◽  
Murine Fibroblasts ◽  
Myc Gene

Induction of quiescent BALB/c 3T3 murine fibroblasts by platelet-derived growth factor (PDGF) or fibroblast growth factor (FGFs) is accompanied by induction of c-myc gene expression. To study the role of c-myc in cell growth, we transfected BALB/c 3T3 cells with a plasmid construct containing a glucocorticoid-inducible c-myc gene. When these transfected cells were growth arrested in PDGF-FGF-freedefined medium, glucocorticoid treatment induced S-phase DNA synthesis. This induction of DNA synthesis was inefficient, and cell proliferation was not evident, suggesting that growth factors act through stimulation of c-myc expression together with other intracellular events.

Bcl-2 protein localizes to the chromosomes of mitotic nuclei and is correlated with the cell cycle in cultured epithelial cell lines

1994 ◽  
Vol 107 (2) ◽  
pp. 363-371
Author(s):  
Q.L. Lu ◽  
A.M. Hanby ◽  
M.A. Nasser Hajibagheri ◽  
S.E. Gschmeissner ◽  
P.J. Lu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Epithelial Cell ◽  
Cell Lines ◽  
Cytoplasmic Localization ◽  
Human Epithelial Cell ◽  
Daughter Cells ◽  
Epithelial Cell Lines ◽  
Cell Immortalization

bcl-2 gene expression confers a survival advantage by preventing cells from entering apoptosis. In contrast to the previously described cytoplasmic localization of Bcl-2 in epithelial cells in vivo, in this study we have demonstrated, in a series of human epithelial cell lines, that Bcl-2 also localizes to mitotic nuclei. Both immunocytochemical and immunoelectron microscopical examinations localize this protein to nuclei and in particular to chromosomes. Nuclear Bcl-2 expression in these cell lines is correlated with the cell cycle. There is relatively strong expression during mitosis, most intense during prophase and metaphase, declining in telophase and then the protein becomes undetectable soon after separation of the two daughter cells. The expression and distribution of Bcl-2 is influenced by treatment with excessive thymidine. These results indicate that Bcl-2 may protect the cells from apoptosis occurring during mitosis and suggest a possible role for the protein in cell immortalization.

Transforming growth factor β1 selectively regulates ferritin gene expression in malignant H-ras-transformed fibrosarcoma cell lines

2000 ◽  
Vol 78 (4) ◽  
pp. 527-535 ◽  
Author(s):  
James Lo ◽  
Robert AR Hurta
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Growth Factor ◽  
Malignant Transformation ◽  
Cell Lines ◽  
Transforming Growth Factor ◽  
Malignant Potential ◽  
Transformed Cells ◽  
Protein Synthesis Inhibitor ◽  
Ferritin Gene

Transforming growth factor β1 is an important growth regulator in many cell types, usually exerting a negative effect on cellular growth. Inhibition of DNA synthesis and cell proliferation is frequently lost during malignant transformation, and in some cases, tumor cell proliferation is actually stimulated by TGF-β1. The present study demonstrates a novel link between alterations in TGF-β1 regulation during malignant conversion, and the expression of ferritin, an important activity involved in a number of biological functions including iron homeostasis and cell-growth control. A series of H-ras-transformed mouse 10 T 1/2 cell lines, exhibiting increasing malignant potential, was investigated for possible TGF-β1-mediated changes in ferritin gene expression. Selective induction of gene expression was observed, since only H-ras-transformed cells with malignant potential exhibited marked elevations in ferritin gene expression, in particular, alterations in H-ferritin gene expression. The regulation of H-ferritin gene expression in response to TGF-β 1 did not involve alterations in transcription, but occurred through mechanisms of post-transcriptional stabilization of the H-ferritin mRNA. Additionally, evidence was obtained for a cycloheximide-sensitive regulator of H-ferritin gene expression, since the presence of this protein synthesis inhibitor increased H-ferritin message levels, and in combination with TGF-β1, cooperated in an additive manner to augment H-ferritin gene expression. These results show for the first time that TGF-β1 can regulate ferritin gene expression in malignant H-ras transformed cells, and suggest a mechanism for growth factor stimulation of malignant cells, in which early alterations in the control of H-ferritin gene expression are important.Key words: TGF-β1, ferritin gene expression, malignant transformation.

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