scholarly journals Dis3L2 regulates cell proliferation and tissue growth through a conserved mechanism

PLoS Genetics ◽  
2020 ◽  
Vol 16 (12) ◽  
pp. e1009297
Author(s):  
Benjamin P. Towler ◽  
Amy L. Pashler ◽  
Hope J. Haime ◽  
Katarzyna M. Przybyl ◽  
Sandra C. Viegas ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Control Cell ◽  
Human Kidney ◽  
Mechanistic Explanation ◽  
Tissue Growth ◽  
Rna Seq ◽  
Wild Type ◽  
Small Cell Lung ◽  
Wing Discs ◽  
Cellular Pathways

Dis3L2 is a highly conserved 3’-5’ exoribonuclease which is mutated in the human overgrowth disorders Perlman syndrome and Wilms’ tumour of the kidney. Using Drosophila melanogaster as a model system, we have generated a new dis3L2 null mutant together with wild-type and nuclease-dead genetic lines in Drosophila to demonstrate that the catalytic activity of Dis3L2 is required to control cell proliferation. To understand the cellular pathways regulated by Dis3L2 to control proliferation, we used RNA-seq on dis3L2 mutant wing discs to show that the imaginal disc growth factor Idgf2 is responsible for driving the wing overgrowth. IDGFs are conserved proteins homologous to human chitinase-like proteins such as CHI3L1/YKL-40 which are implicated in tissue regeneration as well as cancers including colon cancer and non-small cell lung cancer. We also demonstrate that loss of DIS3L2 in human kidney HEK-293T cells results in cell proliferation, illustrating the conservation of this important cell proliferation pathway. Using these human cells, we show that loss of DIS3L2 results in an increase in the PI3-Kinase/AKT signalling pathway, which we subsequently show to contribute towards the proliferation phenotype in Drosophila. Our work therefore provides the first mechanistic explanation for DIS3L2-induced overgrowth in humans and flies and identifies an ancient proliferation pathway controlled by Dis3L2 to regulate cell proliferation and tissue growth.

scholarly journals Dis3L2 regulates cellular proliferation through a PI3-Kinase dependent signalling pathway

2019 ◽  
Author(s):  
Benjamin P. Towler ◽  
Amy L. Pashler ◽  
Hope J. Haime ◽  
Katarzyna M. Przybyl ◽  
Sandra C. Viegas ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cellular Proliferation ◽  
Mechanistic Explanation ◽  
Tissue Growth ◽  
Pi3 Kinase ◽  
Signalling Pathway ◽  
Null Mutant ◽  
Rna Seq ◽  
Small Cell Lung ◽  
Wing Discs

AbstractDis3L2 is a highly conserved 3’-5’ exoribonuclease which is mutated in the human overgrowth disorders Perlman syndrome and Wilms’ tumour. Here, we have generated a new dis3L2 null mutant and a UAS-nuclease-dead line in Drosophila to demonstrate that the catalytic activity of Dis3L2 is required to control proliferation in imaginal discs. Using RNA-seq on dis3L2 mutant wing discs, we show that the imaginal disc growth factor Idgf2 is responsible for driving the wing overgrowth observed in dis3L2 null mutants. IDGFs are conserved proteins homologous to human chitinase-like proteins such as CHI3L1/YKL-40 which are implicated in tissue regeneration as well as cancers including colon cancer and non-small cell lung cancer. We also show that loss of DIS3L2 in human HEK-293T cells results in cell proliferation, illustrating the conservation of this important cell proliferation pathway. Using these human cells we show that loss of DIS3L2 results in an increase in the activity of the PI3-Kinase/AKT signalling pathway, which we subsequently show to also have a role in driving the proliferation phenotype in Drosophila. Our work therefore provides the first mechanistic explanation for DIS3L2-induced overgrowth in humans and flies and identifies an ancient proliferation pathway controlled by Dis3L2 to regulate cell proliferation and tissue growth.

scholarly journals Estrogen-Induced CCN1 Is Critical for Establishment of Endometriosis-Like Lesions in Mice

2014 ◽  
Vol 28 (12) ◽  
pp. 1934-1947 ◽  
Author(s):  
Yuechao Zhao ◽  
Quanxi Li ◽  
Benita S. Katzenellenbogen ◽  
Lester F. Lau ◽  
Robert N. Taylor ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Cell Proliferation ◽  
Growth Factor ◽  
Molecular Mechanisms ◽  
Tissue Growth ◽  
Endometrial Tissue ◽  
Vascular Endothelial ◽  
Wild Type ◽  
Factor C ◽  
Endothelial Growth Factor

Endometriosis is a prevalent gynecological disorder in which endometrial tissue proliferates in extrauterine sites, such as the peritoneal cavity, eventually giving rise to painful, invasive lesions. Dysregulated estradiol (E) signaling has been implicated in this condition. However, the molecular mechanisms that operate downstream of E in the ectopic endometrial tissue are unknown. To investigate these mechanisms, we used a mouse model of endometriosis. Endometrial tissue from donor mice was surgically transplanted on the peritoneal surface of immunocompetent syngeneic recipient mice, leading to the establishment of cystic endometriosis-like lesions. Our studies revealed that treatment with E led to an approximately 3-fold increase in the lesion size within a week of transplantation. E also caused a concomitant stimulation in the expression of connective tissue growth factor/Cyr61/Nov (CCN1), a secreted cysteine-rich matricellular protein, in the lesions. Interestingly, CCN1 is highly expressed in human ectopic endometriotic lesions. To address its role in endometriosis, endometrial tissue from Ccn1-null donor mice was transplanted in wild-type recipient mice. The resulting ectopic lesions were reduced up to 75% in size compared with wild-type lesions due to diminished cell proliferation and cyst formation. Notably, loss of CCN1 also disrupted the development of vascular networks in the ectopic lesions and reduced the expression of several angiogenic factors, such as vascular endothelial growth factor-A and vascular endothelial growth factor-C. These results suggest that CCN1, acting downstream of E, critically controls cell proliferation and neovascularization, which support the growth and survival of endometriotic tissue at ectopic sites. Blockade of CCN1 signaling during the early stages of lesion establishment may provide a therapeutic avenue to control endometriosis.

Clinical, pathological and molecular characterization of long-term survivors with advanced non-small cell lung cancer in a multicenter experience in Madrid: Final results.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20621-e20621
Author(s):  
Juan Moreno ◽  
Santiago Ponce Aix ◽  
Rosa Maria Alvarez Alvarez ◽  
Maria Eugenia Olmedo Garcia ◽  
Sandra Falagan ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Genetic Analysis ◽  
Small Cell Lung Cancer ◽  
Small Cell ◽  
Surfactant Proteins ◽  
Rna Seq ◽  
Wild Type ◽  
Rt Pcr ◽  
Small Cell Lung ◽  
Transcriptome Expression

e20621 Background: Long survivors (LS) in non-small-cell lung cancer (NSCLC), defined as an overall survival (OS) greater than 2 years, are less than 10% in most series. Classical prognosis factors include stage, weight loss and ECOG, but more information is missing in the literature. Recently, EGFR, ALK and ROS 1 population (less than 20%) reach OS longer than 2 years. Immunotherapy has demonstrated very promising results with more LS compared to chemotherapy in first and second line setting. In this study, we focused in the analysis of LS patients with advanced NSCLC EGFR wt (wild type) and ALK nt (non-translocated), defined as those with OS greater than 36 months, in 7 hospitals in Madrid. Methods: In this serie, first of all, we will try to make a clinical, histopathological characterization collecting data from clinical reports according to a previously defined information. In a second step, we will carry out a genetic analysis of these patient samples comparing to an opposite extreme short survivors (SS) samples (OS less than 9 months). Initially, we used a NGS method of RNA-seq technology to identify differentiating profiles of gene expression between the two opposite populations. And finally, we confirmed this preliminary profile by RT-PCR in the rest of samples. Results: Ninety-six patients were initially included. The majority were men, smokers or former with adenocarcinoma and ECOG 0- 1. We have obtained a differential transcriptome expression between samples from 6 LS and 6 SS, resulting 13 over-expressed and 42 down-expressed genes in LS comparing to SS transcriptome expression. Some of the genes involved in this initial profile belong to different cellular pathways: Secretin Receptor, Surfactant Protein, Trefoil Factor 1, Serpin Family, Ca-bindings Protein channel and Toll like Receptor family. Finally, we carried on by RT-PCR in 40 samples of SS and LS survivors and only four genes were significantly down-regulated in SS compared to LS in the multivariate analysis. These 4 genes were related to Surfactant Proteins: SFTPA1 (p = 0.023), SFTPA2 (p = 0.027), SFTPB (p = 0.02) and SFTPC (p = 0.047). Conclusions: We present a sequential genetic analysis of a LS population with NSCLC EGFR wt (wild type) and ALK nt (non-translocated), obtaining a differential RNA seq- and RT-PCR gene profile based on different surfactant proteins expression. A further confirmation in a larger sample is ongoing.

Loss of Stress Sensor GADD45a and GADD45b Accelerates BCR-ABL-Driven Leukemogenesis Via Distinct Signaling and Cellular Pathways.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1217-1217
Author(s):  
Xiaojin Sha ◽  
Barbara Hoffman ◽  
Dan Liebermann
Keyword(s):  
Bone Marrow ◽  
Cell Proliferation ◽  
Signaling Pathways ◽  
Conflicts Of Interest ◽  
Multiple Stressors ◽  
Myelogenous Leukemia ◽  
Ras Signaling ◽  
Wild Type ◽  
Cellular Pathways ◽  
Myeloid Progenitors

Abstract Abstract 1217 The bcr/abl oncogene causes chronic myelogenous leukemia (CML) in humans. BCR/ABL is known to localize to the cytoskeleton and to display a constitutively active tyrosine kinase activity that leads to the recruitment of downstream effectors of cell proliferation and survival. This is accomplished via several adapter proteins and signaling pathways, including Ras, PI3K-AKT, PkD2-NFkB and JAK-STAT5, all of which are believed to participate in the pathogenesis of CML. The complex nature of these signaling pathways and how they contribute to the initiation and progression of CML is only partially understood. The Gadd45 family of genes (Gadd45a, Gadd45b & Gadd45g) encode for small (18 kd) nuclear proteins that are rapidly induced by multiple stressors, including genotoxic and oncogenic stress. They are involved in G2/M cell cycle arrest and apoptosis in response to exogenous stress stimuli through MAPK and JNK/SAPK pathways. Furthermore Gadd45a has been identified as a mediator of oncogenic Ras signaling. GADD45 proteins are upregulated during myeloid lineage terminal differentiation. To investigate if and how GADD45A and GADD45B play a role in the development of CML, syngeneic wild type lethally irradiated mice were reconstituted with wild type, gadd45a or gadd45b null myeloid progenitors transduced with a retrovirally expressed 210-kD BCR/ABL fusion oncoprotein. It was observed that loss of gadd45a or gadd45b accelerates the development of BCR/ABL driven leukemia in wild type recipients. BCR/ABL transformed gadd45a or gadd45b deficient progenitor recipients exhibited significantly accelerated kinetics of increase in the number of WBC and percentage of myeloid blasts in blood compared to mice reconstituted with the same number of wild type bone marrow cells transduced with BCR/ABL. There was also increase in the rate of accumulation of CD11b+Gr1+ cells in the bone marrow and spleen. Using in vitro and in vivo BrdU assays, enhanced proliferation capacity was observed for BCR/ABL transduced gadd45a, but not gadd45b, deficient myeloid progenitors. However, impaired apoptosis was observed both in BCR/ABL transduced gadd45a and gadd45b deficient myeloid progenitors. These results indicate that both gadd45a and gadd45b function as suppressors of the development of BCR/ABL driven CML, where gadd45a appears to suppress CML via a mechanism involving both inhibition of cell proliferation and enhancement of apoptosis, whereas gadd45b appears to effect only apoptosis. Enhanced JNK signaling was observed in both gadd45a and gadd45b deficient progenitors, whereas enhanced p38 and AKT signaling was observed only in gadd45a deficient myeloid progenitors. Taken together, these data indicate that loss of either gadd45a or gadd45b accelerates BCR-ABL driven CML via distinct signaling and cellular pathways. Further elucidating the role Gadd45 stress sensors play in suppressing the development of leukemia should increase understanding of the molecular/cellular pathology BCR/ABL mediated leukemogenesis, and has the potential to lead to the development of new/improved modalities for treatment of leukemia. Disclosures: No relevant conflicts of interest to declare.

The Homodimeric Hematopoietic Cytokine Receptor C-Mpl Requires Cross Phosphorylation in Order to Signal Cell Proliferation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3734-3734
Author(s):  
Justin Persico ◽  
Imawati Budjahardo ◽  
Kenneth Kaushansky
Keyword(s):  
Cell Proliferation ◽  
Cell Line ◽  
Cell Lines ◽  
Western Blotting ◽  
Control Cell ◽  
Janus Kinase ◽  
Cytokine Receptor ◽  
Parental Cell Line ◽  
Wild Type ◽  
Receptor Dimerization

Abstract Objectives: The three primary regulators of hematopoiesis, erythropoietin, granulocyte colony-stimulating factor and thrombopoietin, bind to homodimeric members of the cytokine receptor superfamily and utilize Janus Kinase (JAK) 2 to initiate signaling. Recently, mutations in JAK2, particularly JAK2V617F, were found to contribute to the pathogenesis of the myeloproliferative disorders. In vitro studies have determined that only homodimeric cytokine receptors can support JAK2-mediated cytokine hypersensitivity. As part of a strategy to identify novel approaches to inhibit mutant JAK2 function we tested whether the homodimeric receptors initiate signaling by JAK2 mediated receptor trans-phosphorylation, and whether JAK2V617F escapes this requirement. Methods: We introduced the engineered receptor Myr/FKBPF36V/c-Mplcyto into hematopoietic cell lines containing either wild-type JAK2 or JAK2V617F, a receptor designed to adopt either a monomeric or dimeric state depending on the absence or presence, respectively, of the chemical dimerizer AP20187. To evaluate the effects of receptor dimerization on the growth of wild-type and V617F mutant JAK2 cell lines we measured reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT). If either of the cell lines were able to support cell proliferation in absence of receptor dimerization it would indicate that signaling is initiated by ipsilateral receptor phosphorylation, as opposed to the trans-phosphorylation employed by subfamilies of heterodimeric receptors, such as that for IL-2. Results: The Myr/FKBPF36V/c-Mplcyto receptor construct was subcloned into a retroviral vector, transduced into Baf3, Baf3/JAK2 and Baf3/JAK2V617F cells and spontaneous, IL-3- and AP20187-induced cell proliferation was assessed. Equal expression of the receptor construct in each cell line was confirmed by western blotting. Both Baf3/JAK2- and Baf3/JAK2V617F-derived cell lines transduced with wild type c-Mpl served as controls, and quantitative western blotting was used to verify that equal levels of the two receptor constructs were introduced into the cell lines. Growth factor dependence was confirmed in the control cell lines with both thrombopoietin and IL-3 and was confirmed with IL-3 in the experimental cell lines. There was an increased sensitivity to growth factors in the control cell line containing the JAK2 V617F mutant, consistent with a myeloproliferative phenotype. When Myr/FKBPF36V/Mplcyto was introduced into either Baf3/JAK2 or Baf3/JAK2V617F cells, the cells remained dependent on either IL-3 or AP20187, although maximal rates of cell growth were significantly greater in the Baf3/JAK2V617F/Myr/FKBPF36V/Mplcyto cells than in Baf3/JAK2/Myr/FKBPF36V/Mplcyto cells. The maximal rate of growth of Baf3/JAK2V617F/Myr/FKBPF36V/Mplcyto cells also significantly exceeded that of the Baf3 parental cell line. Furthermore, we found that in the absence of chemically induced dimerization neither Myr/FKBPF36V/c-Mplcyto/JAK2 nor Myr/FKBPF36V/c-Mplcyto JAK2V617F cells proliferated. Conclusions: These results argue that JAK2 induces signaling by trans-phosphorylation of the cytoplasmic domains of c-Mpl and that the kinase hyperactivity displayed by JAK2V617F cannot overcome this requirement. Therefore it may be possible to alter or inhibit trans-phosphorylation and attenuate JAK2V617F-mediated myeloproliferation.

Connective Tissue Growth Factor (CTGF) Is Essential for Self Renewal and Proliferation of Mesenchymal Stromal Cells (MSCs) and Affects Leukemia-Stromal Interactions.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3845-3845 ◽  
Author(s):  
Venkata Lokesh Battula ◽  
Maria da Graca Cabreira ◽  
Zhiqiang Wang ◽  
Wencai Ma ◽  
Juliana Benito ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Vector Control ◽  
Stromal Cells ◽  
Lymphoblastic Leukemia ◽  
Leukemia Cell ◽  
Tissue Growth ◽  
Leukemic Cells ◽  
Wild Type ◽  
Differentiation Potential ◽  
Control Mscs

Abstract Abstract 3845 Connective tissue growth factor (CTGF) is a member of the CCN family of growth factors that are critical regulators of vertebrate development. CTGF is a secreted protein that promotes extracellular matrix production, chemotaxis, cell proliferation and integrin expression. Since CTGF is highly expressed in acute lymphoblastic leukemia (ALL) and CTGF expression levels are related to ALL patient survival (Olga ST et al., Blood, 2007), we hypothesized that CTGF plays a role in regulating stromal cell proliferation and leukemia-stroma interaction. Our first goal was to characterize multipotent mesenchymal stromal cells (MSCs) from CTGF-/- mice, which die soon after birth from respiratory failure due to abnormal skeletal growth. We first attempted to isolate MSCs from BALB/C wild type and CTGF-/- newborn mice (Lvkovic S et al., Development, 2003). While we had no difficulty isolating MSCs from wild type mice, we failed to generate MSCs from CTGF-/- newborns (bone marrow, liver, spleen and thymus). As an alternative approach, we suppressed CTGF in bone marrow derived human MSCs with lenti-virus delivered CTGF shRNA (CTGF-KD-MSCs) and achieved knockdown of ≂f65% compared to vector control cells as determined by RT-PCR. Shortly after transduction (4 days) we started to observe major changes in the phenotype of CTGF-KD-MSCs, which grew 6–7 fold slower compared to vector control MSCs. CTGF-KD-MSCs displayed a significant decrease in the number of cells in S phase (from 14.7% ± 0.8% to 3.5%± 0.4%) and a concomitant increase in the number of G0/1 cells (from 68.8%±1.8% to 82.4%± 1.3%) suggesting a G0 or G1 block. To investigate if CTGF affects expression of MSC surface proteins, we analyzed standard MSC markers including CD105, CD90, CD73, CD44, CD140b, CD166 and CD45 (as a negative marker). Surprisingly, no differences in the expression of these markers in CTGF-KD-MSCs compared to vector control MSCs were observed. To determine if CTGF might regulate gene expression in MSCs, we performed a microarray analysis using Illumina arrays. By gene set analysis methods, we observed significant down regulation (p < 10-9 by the hypergeometric distribution test) in CTGF-KD-MSCs of genes involved in cell cycle progression, most notably in the Gene Ontology lists for ribosomal biogenesis and mitosis. As MSCs are known to differentiate into mesodermal cell lineages, we next tested the differentiation potential of CTGF-KD-MSCs as compared to the vector control MSCs. Following standard differentiation protocols, both CTGF-KD- and vector control-MSCs differentiated into osteoblasts and chondrocytes with no differences in their ability to differentiate into these lineages; whereas, CTGF-KD-MSCs showed 6–7 fold increase in their adipocyte differentiation potential compared to vector control MSCs. Another property of MSCs is to self-renew and generate colony forming units-fibroblast like (CFU-F). Fifty or 100 cells of either CTGF-KD-MSCs or vector control MSCs were seeded in alpha-MEM with 10% serum. After 2 weeks of culture in alpha-MEM with 10% serum, the resulting fibroblast-like colonies were counted. Vector control MSCs generated ≂f30-fold higher CFU-F compared to CTGF-KD-MSCs indicating that CTGF-KD-MSCs lack the ability to self renew. Next we determined if suppression of CTGF might impede leukemia cell migration to MSCs. Using standard trans-well assays, we examined human pre-B acute lymphoblastic leukemia (ALL) derived REH cells and found that they migrated 45% ± 4% less to CTGF-KD-MSCs compared to control MSCs. These findings suggest that CTGF plays a major role in stromal cell proliferation, self renewal and adipocyte differentiation of MSCs. In addition, CTGF is involved in leukemia cell migration towards MSCs and inhibition of CTGF impairs the migration of leukemic cells towards stromal cells and thereby provides opportunities to prevent homing of leukemic cells and sensitize them to chemotherapy. Disclosures: Andreeff: MyeloRx LLC: Consultancy, participant in research under an NCI SBIR Contract to MyeloRx LLC.

scholarly journals MSTN mutant promoted bovine muscle satellite cell proliferation by regulating the binding of SMAD2/SMAD3 with CDKN1C

2021 ◽  
Author(s):  
Li Gao ◽  
Miao-Miao Yang ◽  
Ming-Juan Gu ◽  
Yun-Peng Liu ◽  
Cai-Hong Bu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Chromatin Immunoprecipitation ◽  
Muscle Development ◽  
Chip Assay ◽  
Rna Seq ◽  
Wild Type ◽  
Muscle Satellite Cell ◽  
Bovine Muscle ◽  
Expression Of Genes

Abstract Background: Myostatin (MSTN), also known as growth/differentiation factor 8, mostly expressed in skeletal muscle and plays negative roles in regulation of muscle development. Previous studies had proved that MSTN have important effect on cell proliferation. Therefore we aimed to investigate the mechanism of MSTN in regulating the proliferation of bovine muscle satellite cells (MSCs).Methods: Bovine MSCs of MSTN mutant (MT) and wild type (WT) were obtained, we detected the cell proliferation and cell cycle by EdU proliferation assay and Flow cytometry. Then we detected the expression of genes associated with cell cycle by Real-time PCR and Western blotting . RNA-seq and Chromatin immunoprecipitation (ChIP)assay were performed to research the mechanism of MSTN in regulating the cell proliferation. Results: In this study, we found that MSTN mutant promoted the proliferation of MSCs. The expression of CyclinA, CyclinD and CyclinE were all increased after MSTN mutant, while the expression of CDKN1C (P57), CDKN2A, CDKN2C and CDKN2D were down-regulated, which were consistent with the promotion of cell proliferation. Among these genes, CDKN1C(P57) down-regulated most significantly. RNA-seq results showed that MSTN mutant affected the SMAD binding, so we performed ChIP-qPCR and demonstrated that the SMAD2/SMAD3 transcription factor combined with the promoter of CDKN1C thus to increase the expression of CDKN1C, this demonstrating that MSTN regulated the expression of CDKN1C through SMAD2/SMAD3 complex. Finally, overexpression of SMAD3 in wild type cells increased the expression of CDKN1C, further suggested that SMAD3 regulated the expression of CDKN1C. Conclusion: MSTN mutant down-regulated the expression of SMAD2/SMAD3, then reduced the promotion of SMAD2/SMAD3 to the expression of CDKN1C, thus to inhibit the expression of CDKN1C, then promoting the cell cycle.

scholarly journals The bantam Gene Regulates Drosophila Growth

Genetics ◽  
2002 ◽  
Vol 161 (4) ◽  
pp. 1527-1537 ◽  
Author(s):  
David R Hipfner ◽  
Katrin Weigmann ◽  
Stephen M Cohen
Keyword(s):  
Growth Rate ◽  
Cell Proliferation ◽  
Cell Size ◽  
Genetic Interaction ◽  
Cell Number ◽  
Tissue Growth ◽  
Cellular Growth ◽  
Wild Type ◽  
Regulation Of Growth

Abstract We report here the consequences of mutations of a novel locus, named bantam, whose product is involved in the regulation of growth in Drosophila. bantam mutant animals are smaller than wild type, due to a reduction in cell number but not cell size, and do not have significant disruptions in patterning. Conversely, overexpression of the bantam product using the EP element EP(3)3622 causes overgrowth of wing and eye tissue. Overexpression in clones of cells results in an increased rate of cell proliferation and a matched increase in cellular growth rate, such that the resulting tissue is composed of more cells of a size comparable to wild type. These effects are strikingly similar to those associated with alterations in the activity of the cyclinD-cdk4 complex. However, epistasis and genetic interaction analyses indicate that bantam and cyclinD-cdk4 operate independently. Thus, the bantam locus represents a novel regulator of tissue growth.

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