Msx homeobox genes inhibit differentiation through upregulation ofcyclin D1

Development ◽  
2001 ◽  
Vol 128 (12) ◽  
pp. 2373-2384 ◽  
Author(s):  
Gezhi Hu ◽  
Hansol Lee ◽  
Sandy M. Price ◽  
Michael M. Shen ◽  
Cory Abate-Shen
Keyword(s):  
Cell Cycle ◽  
Cyclin D1 ◽  
Cellular Proliferation ◽  
Homeobox Genes ◽  
Mammary Epithelium ◽  
Cell Types ◽  
Proliferation And Differentiation ◽  
Tumor Virus ◽  
Mutant Phenotypes ◽  
Mmtv Ltr

During development, patterning and morphogenesis of tissues are intimately coordinated through control of cellular proliferation and differentiation. We describe a mechanism by which vertebrate Msx homeobox genes inhibit cellular differentiation by regulation of the cell cycle. We show that misexpression of Msx1 via retroviral gene transfer inhibits differentiation of multiple mesenchymal and epithelial progenitor cell types in culture. This activity of Msx1 is associated with its ability to upregulate cyclin D1 expression and Cdk4 activity, while Msx1 has minimal effects on cellular proliferation. Transgenic mice that express Msx1 under the control of the mouse mammary tumor virus long terminal repeat (MMTV LTR) display impaired differentiation of the mammary epithelium during pregnancy, which is accompanied by elevated levels of cyclin D1 expression. We propose that Msx1 gene expression maintains cyclin D1 expression and prevents exit from the cell cycle, thereby inhibiting terminal differentiation of progenitor cells. Our model provides a framework for reconciling the mutant phenotypes of Msx and other homeobox genes with their functions as regulators of cellular proliferation and differentiation during embryogenesis.

scholarly journals Cellular Functions of OCT-3/4 Regulated by Ubiquitination in Proliferating Cells

Cancers ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 663
Author(s):  
Kwang-Hyun Baek ◽  
Jihye Choi ◽  
Chang-Zhu Pei
Keyword(s):  
Stem Cells ◽  
Cellular Proliferation ◽  
Critical Role ◽  
Embryonic Stem ◽  
Cell Types ◽  
Ubiquitin Proteasome System ◽  
Specific Cell ◽  
Cellular Mechanisms ◽  
Proliferating Cells ◽  
Proliferation And Differentiation

Octamer-binding transcription factor 3/4 (OCT-3/4), which is involved in the tumorigenesis of somatic cancers, has diverse functions during cancer development. Overexpression of OCT-3/4 has been detected in various human somatic tumors, indicating that OCT-3/4 activation may contribute to the development and progression of cancers. Stem cells can undergo self-renewal, pluripotency, and reprogramming with the help of at least four transcription factors, OCT-3/4, SRY box-containing gene 2 (SOX2), Krüppel-like factor 4 (KLF4), and c-MYC. Of these, OCT-3/4 plays a critical role in maintenance of undifferentiated state of embryonic stem cells (ESCs) and in production of induced pluripotent stem cells (iPSCs). Stem cells can undergo partitioning through mitosis and separate into specific cell types, three embryonic germ layers: the endoderm, the mesoderm, and the trophectoderm. It has been demonstrated that the stability of OCT-3/4 is mediated by the ubiquitin-proteasome system (UPS), which is one of the key cellular mechanisms for cellular homeostasis. The framework of the mechanism is simple, but the proteolytic machinery is complicated. Ubiquitination promotes protein degradation, and ubiquitination of OCT-3/4 leads to regulation of cellular proliferation and differentiation. Therefore, it is expected that OCT-3/4 may play a key role in proliferation and differentiation of proliferating cells.

scholarly journals MicroRNA let-7b regulates neural stem cell proliferation and differentiation by targeting nuclear receptor TLX signaling

2010 ◽  
Vol 107 (5) ◽  
pp. 1876-1881 ◽  
Author(s):  
Chunnian Zhao ◽  
GuoQiang Sun ◽  
Shengxiu Li ◽  
Ming-Fei Lang ◽  
Su Yang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Stem Cell ◽  
Cyclin D1 ◽  
Neural Stem Cell ◽  
Neural Differentiation ◽  
Stem Cell Proliferation ◽  
Neural Stem Cell Proliferation ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation

Neural stem cell self-renewal and differentiation is orchestrated by precise control of gene expression involving nuclear receptor TLX. Let-7b, a member of the let-7 microRNA family, is expressed in mammalian brains and exhibits increased expression during neural differentiation. However, the role of let-7b in neural stem cell proliferation and differentiation remains unknown. Here we show that let-7b regulates neural stem cell proliferation and differentiation by targeting the stem cell regulator TLX and the cell cycle regulator cyclin D1. Overexpression of let-7b led to reduced neural stem cell proliferation and increased neural differentiation, whereas antisense knockdown of let-7b resulted in enhanced proliferation of neural stem cells. Moreover, in utero electroporation of let-7b to embryonic mouse brains led to reduced cell cycle progression in neural stem cells. Introducing an expression vector of Tlx or cyclin D1 that lacks the let-7b recognition site rescued let-7b-induced proliferation deficiency, suggesting that both TLX and cyclin D1 are important targets for let-7b-mediated regulation of neural stem cell proliferation. Let-7b, by targeting TLX and cyclin D1, establishes an efficient strategy to control neural stem cell proliferation and differentiation.

Expression of polo-like kinase (PLK) in the mouse placenta and ovary

1999 ◽  
Vol 11 (1) ◽  
pp. 31 ◽  
Author(s):  
Noriyuki Takai ◽  
Jun Yoshimatsu ◽  
Yoshihiro Nishida ◽  
Isao Miyakawa ◽  
Ryoji Hamanaka ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cellular Proliferation ◽  
Cultured Cells ◽  
Embryo Implantation ◽  
Cell Types ◽  
Nuclear Antigen ◽  
Ovarian Stroma ◽  
Mouse Placenta ◽  
Trophoblastic Tissue

The polo-like kinase (PLK) is a mammalian serine/threonine kinase involved in cell cycle regulation. Much evidence for the role of PLK in the cell cycle has come from studies of cultured cells; however, little is known about its function or even expression in vivo . The present study examined the features of PLK expression in the mouse placenta and ovary. Immunohistochemical studies showed that PLK is highly expressed in the basement membrane of the endometrial gland, in some endothelial cells, in endometrium after embryo implantation, in trophoblastic tissue invading the decidua, in the ovarian stroma and in some lutein bodies. In contrast, PLK was not detectable by immunohistochemistry in endometrial stroma before decidualization, in decidua, in trophoblastic tissue not invading the decidua or in ovarian follicles. PLK expression seemed to be correlated with the expression of proliferation cellular nuclear antigen (PCNA) in many placental and ovarian cells, reflecting a role in cellular proliferation. Nevertheless, in ovarian stroma and lutein bodies where PCNA was not expressed, PLK was strongly expressed. This finding indicates that PLK may have some post mitotic functions in certain specialized cell types.

scholarly journals Positive and negative regulation of c-Myb by cyclin D1, cyclin-dependent kinases, and p27 Kip1

Blood ◽  
2005 ◽  
Vol 105 (10) ◽  
pp. 3855-3861 ◽  
Author(s):  
Wanli Lei ◽  
Fan Liu ◽  
Scott A. Ness
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Cyclin D1 ◽  
Target Genes ◽  
Cell Types ◽  
Myb Transcription Factor ◽  
Human T Cells ◽  
Transforming Activity ◽  
Differentiation And Proliferation ◽  
P27 Kip1

AbstractThe c-Myb transcription factor controls differentiation and proliferation in hematopoietic and other cell types and has latent transforming activity, but little is known about its regulation during the cell cycle. Here, c-Myb was identified as part of a protein complex from human T cells containing the cyclin-dependent kinase (CDK) CDK6. Assays using model reporter constructs as well as endogenous target genes showed that the activity of c-Myb was inhibited by cyclin D1 plus CDK4 or CDK6 but stimulated by expression of the CDK inhibitors p16 Ink4a, p21 Cip1, or p27 Kip1. Mapping experiments identified a highly conserved region in c-Myb which, when transferred to the related A-Myb transcription factor, also rendered it responsive to CDKs and p27. The results suggest that c-Myb activity is directly regulated by cyclin D1 and CDKs and imply that c-Myb activity is regulated during the cell cycle in hematopoietic cells.

scholarly journals Inhibition of Cyclin D1 Kinase Activity Is Associated with E2F-Mediated Inhibition of Cyclin D1 Promoter Activity through E2F and Sp1

1998 ◽  
Vol 18 (6) ◽  
pp. 3212-3222 ◽  
Author(s):  
Genichi Watanabe ◽  
Chris Albanese ◽  
Richard J. Lee ◽  
Anne Reutens ◽  
Gino Vairo ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cyclin D1 ◽  
Promoter Activity ◽  
Cell Cycle Progression ◽  
Cellular Proliferation ◽  
Kinase Activity ◽  
D1 Protein ◽  
Binding Domain ◽  
Cycle Progression ◽  
Amino Terminal

ABSTRACT Coordinated interactions between cyclin-dependent kinases (Cdks), their target “pocket proteins” (the retinoblastoma protein [pRB], p107, and p130), the pocket protein binding E2F-DP complexes, and the Cdk inhibitors regulate orderly cell cycle progression. The cyclin D1 gene encodes a regulatory subunit of the Cdk holoenzymes, which phosphorylate the tumor suppressor pRB, leading to the release of free E2F-1. Overexpression of E2F-1 can induce apoptosis and may either promote or inhibit cellular proliferation, depending upon the cell type. In these studies overexpression of E2F-1 inhibited cyclin D1-dependent kinase activity, cyclin D1 protein levels, and promoter activity. The DNA binding domain, the pRB pocket binding region, and the amino-terminal Sp1 binding domain of E2F-1 were required for full repression of cyclin D1. Overexpression of pRB activated the cyclin D1 promoter, and a dominant interfering pRB mutant was defective in cyclin D1 promoter activation. Two regions of the cyclin D1 promoter were required for full E2F-1-dependent repression. The region proximal to the transcription initiation site at −127 bound Sp1, Sp3, and Sp4, and the distal region at −143 bound E2F-4–DP-1–p107. In contrast with E2F-1, E2F-4 induced cyclin D1 promoter activity. Differential regulation of the cyclin D1 promoter by E2F-1 and E2F-4 suggests that E2Fs may serve distinguishable functions during cell cycle progression. Inhibition of cyclin D1 abundance by E2F-1 may contribute to an autoregulatory feedback loop to reduce pRB phosphorylation and E2F-1 levels in the cell.

scholarly journals NF-κB Controls Cell Growth and Differentiation through Transcriptional Regulation of Cyclin D1

1999 ◽  
Vol 19 (8) ◽  
pp. 5785-5799 ◽  
Author(s):  
Denis C. Guttridge ◽  
Chris Albanese ◽  
Julie Y. Reuther ◽  
Richard G. Pestell ◽  
Albert S. Baldwin
Keyword(s):  
Cell Cycle ◽  
Cell Growth ◽  
Cyclin D1 ◽  
Cellular Proliferation ◽  
Myogenic Differentiation ◽  
C2c12 Myoblast ◽  
Transcriptional Level ◽  
Diploid Fibroblasts ◽  
Cell Growth And Differentiation ◽  
Differentiation Model

ABSTRACT Accumulating evidence implicates the transcription factor NF-κB as a positive mediator of cell growth, but the molecular mechanism(s) involved in this process remains largely unknown. Here we use both a skeletal muscle differentiation model and normal diploid fibroblasts to gain insight into how NF-κB regulates cell growth and differentiation. Results obtained with the C2C12 myoblast cell line demonstrate that NF-κB functions as an inhibitor of myogenic differentiation. Myoblasts generated to lack NF-κB activity displayed defects in cellular proliferation and cell cycle exit upon differentiation. An analysis of cell cycle markers revealed that NF-κB activates cyclin D1 expression, and the results showed that this regulatory pathway is one mechanism by which NF-κB inhibits myogenesis. NF-κB regulation of cyclin D1 occurs at the transcriptional level and is mediated by direct binding of NF-κB to multiple sites in the cyclin D1 promoter. Using diploid fibroblasts, we demonstrate that NF-κB is required to induce cyclin D1 expression and pRb hyperphosphorylation and promote G1-to-S progression. Consistent with results obtained with the C2C12 differentiation model, we show that NF-κB also promotes cell growth in embryonic fibroblasts, correlating with its regulation of cyclin D1. These data therefore identify cyclin D1 as an important transcriptional target of NF-κB and reveal a mechanism to explain how NF-κB is involved in the early phases of the cell cycle to regulate cell growth and differentiation.

New twist in the regulation of cyclin D1

2010 ◽  
Vol 1 (5-6) ◽  
pp. 403-409 ◽  
Author(s):  
Jun-ya Kato ◽  
Noriko Yoneda-Kato
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cyclin D1 ◽  
Regulatory Mechanism ◽  
Physiological Role ◽  
Cell Types ◽  
Cellular Function ◽  
The Novel ◽  
Extracellular Signals

AbstractAmong the cell cycle-related mammalian cyclins, cyclin D1 is more closely connected with cell proliferation in response to extracellular signals than the cell cycle clock itself. Because both its mRNA and protein are labile, the intracellular abundance of cyclin D1 is thought to be largely regulated at the level of transcription. However, recent findings suggest that, in certain cell types, cyclin D1 is post-translationally regulated, and a disturbance of this regulatory mechanism induces aberrant entry into the cell cycle and proliferation, sometimes leading to diseases such as cancer. In this review, we summarize recent findings and discuss the physiological role and cellular function of the novel mechanism of regulation of cyclin D1 in terms of the control of cell proliferation.

scholarly journals Adhesion-dependent cell cycle progression linked to the expression of cyclin D1, activation of cyclin E-cdk2, and phosphorylation of the retinoblastoma protein.

1996 ◽  
Vol 133 (2) ◽  
pp. 391-403 ◽  
Author(s):  
X Zhu ◽  
M Ohtsubo ◽  
R M Böhmer ◽  
J M Roberts ◽  
R K Assoian
Keyword(s):  
Cell Cycle ◽  
Growth Factors ◽  
Cyclin D1 ◽  
Cell Cycle Progression ◽  
Cyclin E ◽  
Retinoblastoma Protein ◽  
Cell Types ◽  
S Phase ◽  
Cycle Basis ◽  
Nonadherent Cells

Growth factors and cell anchorage jointly regulate transit through G1 in almost all cell types, but the cell cycle basis for this combined requirement remains largely uncharacterized. We show here that cell adhesion and growth factors jointly regulate the cyclin D1- and E-dependent kinases. Adhesion to substratum regulates both the induction and translation of cyclin D1 mRNA. Nonadherent cells fail to phosphorylate the retinoblastoma protein (Rb), and enforced expression of cyclin D1 rescues Rb phosphorylation and entry into S phase when G1 cells are cultured in the absence of substratum. Nonadherent cells also fail to activate the cyclin E-associated kinase, and this effect can be linked to an increased association of the cdk inhibitors, p21 and p27. These data describe a striking convergence in the cell cycle controls used by the two major signal transduction systems responsible for normal and abnormal cell growth. Taken together with our previous studies showing adhesion-dependent expression of cyclin A, they also establish the cell cycle basis for explaining the combined requirement for growth factors and the extracellular matrix in transit through the Rb checkpoint, entry into S phase, and anchorage-dependent growth.

scholarly journals Human adiponectin inhibits cell growth and induces apoptosis in human endometrial carcinoma cells, HEC-1-A and RL95–2

2007 ◽  
Vol 14 (3) ◽  
pp. 713-720 ◽  
Author(s):  
Li Cong ◽  
Jessica Gasser ◽  
Jessica Zhao ◽  
Baofeng Yang ◽  
Fanghong Li ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Endometrial Cancer ◽  
Cyclin D1 ◽  
Endometrial Carcinoma ◽  
Cell Lines ◽  
Prolonged Exposure ◽  
D1 Protein ◽  
Cell Types ◽  
Similar Treatment ◽  
Inhibition Of Growth

Obesity is one of the well-established risk factors for endometrial cancer. Recent clinical studies have demonstrated that circulating adiponectin concentrations are inversely correlated with the incidence of endometrial carcinoma. Such epidemiological findings are consistent with the paradoxical observations that adiponectin levels are reduced in obesity. This study investigated the direct effects of adiponectin on two endometrial carcinoma cell lines, HEC-1-A and RL95–2. These cell lines express both variants of adiponectin receptors, adipo-R1 and adipo-R2. Adiponectin treatment leads to suppression of cell proliferation in both cell types, which is primarily due to the significant increase of cell populations at G1/G0-phase and to the induction of apoptosis. The inhibition of growth in these two cell lines appears to be mediated by different signaling pathways. Although adiponectin treatment markedly increases the phosphorylation (Thr172) of AMP-activated protein kinase α in both HEC-1-A and RL95–2 within 30 min, prolonged exposure (48 h) leads to inactivation of Akt as well as reduction of cyclin D1 protein expression in HEC-1-A cells. In contrast, similar treatment of RL95–2 cells with adiponectin, while having no effects on Akt activity and cyclin D1 expression, causes a decrease in cyclin E2 expression and the activity of mitogen-activated kinase (p42/44). We conclude that adiponectin exerts direct anti-proliferative effects on HEC-1-A and RL95–2 cells by inducing cell cycle arrest and apoptosis. Depending on the genotypes of the endometrial cancer cells, the inhibitory effects of adiponectin are associated with the reduction of different pro-growth regulators of cell cycle and signaling proteins. Our study thus provides a cellular mechanism underlying the linkages between endometrial cancer and obesity.

scholarly journals Epithelial Xbp1 Is Required for Cellular Proliferation and Differentiation during Mammary Gland Development

2015 ◽  
Vol 35 (9) ◽  
pp. 1543-1556 ◽  
Author(s):  
Daisuke Hasegawa ◽  
Veronica Calvo ◽  
Alvaro Avivar-Valderas ◽  
Abigale Lade ◽  
Hsin-I Chou ◽  
...  
Keyword(s):  
Mammary Gland ◽  
Mammary Gland Development ◽  
Cellular Proliferation ◽  
Prolactin Receptor ◽  
Mammary Epithelium ◽  
Branching Morphogenesis ◽  
Direct Function ◽  
Proliferation And Differentiation ◽  
The Unfolded Protein Response ◽  
Gland Development

Xbp1, a key mediator of the unfolded protein response (UPR), is activated by IRE1α-mediated splicing, which results in a frameshift to encode a protein with transcriptional activity. However, the direct function of Xbp1 in epithelial cells during mammary gland development is unknown. Here we report that the loss of Xbp1 in the mammary epithelium through targeted deletion leads to poor branching morphogenesis, impaired terminal end bud formation, and spontaneous stromal fibrosis during the adult virgin period. Additionally, epithelial Xbp1 deletion induces endoplasmic reticulum (ER) stress in the epithelium and dramatically inhibits epithelial proliferation and differentiation during lactation. The synthesis of milk and its major components, α/β-casein and whey acidic protein (WAP), is significantly reduced due to decreased prolactin receptor (Prlr) and ErbB4 expression in Xbp1-deficient mammary epithelium. Reduction of Prlr and ErbB4 expression and their diminished availability at the cell surface lead to reduced phosphorylated Stat5, an essential regulator of cell proliferation and differentiation during lactation. As a result, lactating mammary glands in these mice produce less milk protein, leading to poor pup growth and postnatal death. These findings suggest that the loss of Xbp1 induces a terminal UPR which blocks proliferation and differentiation during mammary gland development.

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