Abstract:
:Inactivating mutations within the von Hippel-Lindau (VHL) tumor suppressor gene predispose patients to develop a variety of highly vascularized tumors. pVHL targets alpha subunits of the heterodimeric transcription factor hypoxia-inducible factor (HIF), a critical regulator of energy metabolism, angiogenesis, hematopoiesis, and oxygen (O(2)) delivery, for ubiquitin-mediated degradation in an O(2)-dependent manner. To investigate the role of Vhl in cellular proliferation and tumorigenesis, we utilized mouse embryonic fibroblasts (MEFs), a common tool for analyzing cell cycle regulation, and generated Vhl(-)(/)(-) MEF-derived fibrosarcomas. Surprisingly, growth of both Vhl(-)(/)(-) MEFs and fibrosarcomas was impaired, although tumor vascularity was increased. Decreased proliferation of Vhl(-)(/)(-) MEFs was correlated with an overexpression of cyclin kinase inhibitors (CKIs) p21 and p27. The transcription of p21 and p27 is inhibited by c-Myc; therefore, the induction of CKIs was attributed to the ability of HIF to antagonize c-Myc activity. Indeed, p21 mRNA levels were elevated under normoxia in Vhl(-)(/)(-) MEFs, while c-Myc transcriptional activity was markedly reduced. Gene silencing of HIF-1alpha by small interfering RNA reduced p21 and p27 protein and mRNA levels in Vhl(-)(/)(-) MEFs. The induction of p21 and p27, mediated by constitutive activation of the HIF pathway, provides a mechanism for the decreased proliferation rates of Vhl(-)(/)(-) MEFs and fibrosarcomas. These results demonstrate that a loss of pVHL can induce growth arrest in certain cells types, which suggests that additional genetic mutations are necessary for VHL-associated tumorigenesis.
journal_name
Mol Cell Bioljournal_title
Molecular and cellular biologyauthors
Mack FA,Patel JH,Biju MP,Haase VH,Simon MCdoi
10.1128/MCB.25.11.4565-4578.2005subject
Has Abstractpub_date
2005-06-01 00:00:00pages
4565-78issue
11eissn
0270-7306issn
1098-5549pii
25/11/4565journal_volume
25pub_type
杂志文章abstract::The Drosophila melanogaster Myb-MuvB/dREAM complex (MMB/dREAM) participates in both the activation and repression of developmentally regulated genes and origins of DNA replication. Mutants in MMB subunits exhibit diverse phenotypes, including lethality, eye defects, reduced fecundity, and sterility. Here, we used P-el...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.00432-12
更新日期:2012-08-01 00:00:00
abstract::Wnt signaling plays an important role in the regulation of bone formation and bone mass. The mechanisms that regulate canonical Wnt signaling in osteoblasts are not fully understood. We show here a novel mechanism by which the adhesion molecule N-cadherin interacts with the Wnt coreceptor LRP5 and regulates canonical ...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.00349-08
更新日期:2009-02-01 00:00:00
abstract::Oncogenic activation of the mitogen-activated protein (MAP) kinase cascade in murine fibroblasts initiates a senescence-like cell cycle arrest that depends on the ARF/p53 tumor suppressor pathway. To investigate whether p53 is sufficient to induce senescence, we introduced a conditional murine p53 allele (p53(val135))...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.22.10.3497-3508.2002
更新日期:2002-05-01 00:00:00
abstract::Five mouse alpha-tubulin isotypes are described, each distinguished by the presence of unique amino acid substitutions within the coding region. Most, though not all of these isotype-specific amino acids, are clustered at the carboxy terminus. One of the alpha-tubulin isotypes described is expressed exclusively in tes...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.6.7.2409
更新日期:1986-07-01 00:00:00
abstract::We have characterized a pathway for nuclear export of the glucocorticoid receptor (GR) in mammalian cells. This pathway involves the Ca2+ -binding protein calreticulin (CRT), which directly contacts the DNA binding domain (DBD) of GR and facilitates its delivery from the nucleus to the cytoplasm. In the present study,...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.22.17.6286-6297.2002
更新日期:2002-09-01 00:00:00
abstract::Wnt/β-catenin signaling is a critical regulator of skeletal physiology. However, previous studies have mainly focused on its roles in osteoblasts, while its specific function in osteoclasts is unknown. This is a clinically important question because neutralizing antibodies against Wnt antagonists are promising new dru...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.05980-11
更新日期:2011-12-01 00:00:00
abstract::We used a transient-expression assay to identify two estrogen response elements (EREs) associated with the major chicken vitellogenin gene (VTGII). Each element was characterized by its ability to confer estrogen responsiveness when cloned in either orientation next to a chimeric reporter gene consisting of the herpes...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.8.3.1123
更新日期:1988-03-01 00:00:00
abstract::Transcriptional factors of the NFAT family play an important role in regulating the expression of several cytokine genes during the immune response, such as the genes for interleukin 2 (IL-2) and IL-4, among others. Upon antigen stimulation, precursor CD4+ T helper (pTh) cells proliferate and differentiate into two po...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.17.3.1522
更新日期:1997-03-01 00:00:00
abstract::A special group of mitochondrial outer membrane proteins spans the membrane once, exposing soluble domains to both sides of the membrane. These proteins are synthesized in the cytosol and then inserted into the membrane by an unknown mechanism. To identify proteins that are involved in the biogenesis of the single-spa...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.00227-13
更新日期:2013-10-01 00:00:00
abstract::Rad53 of Saccharomyces cerevisiae is a checkpoint kinase whose structure and function are conserved among eukaryotes. When a cell detects damaged DNA, Rad53 activity is dramatically increased, which ultimately leads to changes in DNA replication, repair, and cell division. Despite its central role in checkpoint signal...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.23.10.3405-3416.2003
更新日期:2003-05-01 00:00:00
abstract::Study of the mechanism(s) of genomic instability induced by the c-myc proto-oncogene has the potential to shed new light on its well-known oncogenic activity. However, an underlying mechanism(s) for this phenotype is largely unknown. In the present study, we investigated the effects of c-Myc overexpression on the DNA ...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.22.6.1819-1833.2002
更新日期:2002-03-01 00:00:00
abstract::RNA interference with one of the eight Caenorhabditis elegans linker histone genes triggers desilencing of a repetitive transgene and developmental defects in the hermaphrodite germ line. These characteristics are similar to the phenotype of the C. elegans Polycomb group genes mes-2, mes-3, mes-4, and mes-6 (M. A. Jed...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.01713-06
更新日期:2007-03-01 00:00:00
abstract::We isolated a Drosophila fickleP (ficP) mutant with a shortened copulatory duration and reduced adult-stage life span. The reduced copulatory duration is ascribable to incomplete fusion of the left and right halves of the apodeme that holds the penis during copulation. ficP is an intronic mutation occurring in the Btk...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.19.6.4405
更新日期:1999-06-01 00:00:00
abstract::Sensing of extracellular glucose is necessary for cells to adapt to glucose variation in their environment. In the respiratory yeast Kluyveromyces lactis, extracellular glucose controls the expression of major glucose permease gene RAG1 through a cascade similar to the Saccharomyces cerevisiae Snf3/Rgt2/Rgt1 glucose s...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.00515-14
更新日期:2015-02-01 00:00:00
abstract::ARGRI, ARGRII, and ARGRIII proteins regulate the expression of arginine anabolic and catabolic genes. The integrity of these three proteins is required to observe the formation of a DNA-protein complex with the different promoters of arginine coregulated genes. A study of deletions and point mutations created in the 5...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.11.5.2852
更新日期:1991-05-01 00:00:00
abstract::A strong block to the elongation of nascent RNA transcripts by RNA polymerase II occurs in the 5' part of the mammalian c-fos proto-oncogene. In addition to the control of initiation, this mechanism contributes to transcriptional regulation of the gene. In vitro transcription experiments using nuclear extracts and pur...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.11.5.2832
更新日期:1991-05-01 00:00:00
abstract::As a prominent characteristic of cell life, the regulation of cell quiescence is important for proper development, regeneration, and stress resistance and may play a role in certain degenerative diseases. However, the mechanism underlying quiescence remains largely unknown. Encysted embryos of Artemia are useful for s...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.00453-16
更新日期:2017-03-17 00:00:00
abstract::We have characterized the putative AP1 site in the backbone of pUC plasmids and found unique regulatory effects. The site, which mapped to a 19-bp region around nucleotide 37, conferred transcriptional activation by Jun or Jun/Fos that was boosted up to fivefold by unliganded thyroid hormone receptor (TR). Thyroid hor...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.13.5.3042
更新日期:1993-05-01 00:00:00
abstract::The yeast nuclear gene YME1 was one of six genes recently identified in a screen for mutations that elevate the rate at which DNA escapes from mitochondria and migrates to the nucleus. yme1 mutations, including a deletion, cause four known recessive phenotypes: an elevation in the rate at which copies of TRP1 and ARS1...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.13.9.5418
更新日期:1993-09-01 00:00:00
abstract::Simultaneous resistance to an array of drugs with different cytotoxic activities is a property of Saccharomyces cerevisiae, in which the protein Pdr3p has recently been shown to play a role as a transcriptional regulator. We provide evidence that the yeast PDR3 gene, which encodes a zinc finger transcription factor im...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.15.8.4043
更新日期:1995-08-01 00:00:00
abstract::The promoter region of the human parathyroid hormone gene was fused to the Escherichia coli neo gene and introduced into GH4C1 rat pituitary and human HeLa cells. Both TATA boxes of the human parathyroid hormone gene accurately directed transcription in GH4C1 cells; the parathyroid hormone promoter was inactive in HeL...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.6.5.1830
更新日期:1986-05-01 00:00:00
abstract::The Cockayne syndrome B protein (CSB) is required for coupling DNA excision repair to transcription in a process known as transcription-coupled repair (TCR). Cockayne syndrome patients show UV sensitivity and severe neurodevelopmental abnormalities. CSB is a DNA-dependent ATPase of the SWI2/SNF2 family. SWI2/SNF2-like...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.20.20.7643-7653.2000
更新日期:2000-10-01 00:00:00
abstract::Reduction of the survival of motor neurons (SMN) protein levels causes the motor neuron degenerative disease spinal muscular atrophy, the severity of which correlates with the extent of reduction in SMN. SMN, together with Gemins 2 to 7, forms a complex that functions in the assembly of small nuclear ribonucleoprotein...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.25.13.5543-5551.2005
更新日期:2005-07-01 00:00:00
abstract::R2 non-long terminal repeat retrotransposable elements insert at a unique site in the 28S rRNA genes of insects. The protein encoded by the single open reading frame of R2 is capable of conducting the initial steps of its integration in vitro. The protein nicks the noncoding strand of the 28S target DNA (the strand wh...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.16.9.4726
更新日期:1996-09-01 00:00:00
abstract::We investigated two phenotypically distinct types of diphtheria toxin-resistant mutants of Chinese hamster cells and compared their resistance with that of naturally resistant mouse cells. All are resistant due to a defect in the process of internalization and delivery of toxin to its target in the cytosol, elongation...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.3.7.1283
更新日期:1983-07-01 00:00:00
abstract::The pocket protein family of tumor suppressors, and Rb specifically, have been implicated as controlling terminal differentiation in many tissues, including the heart. To establish the biological functions of Rb in the heart and overcome the early lethality caused by germ line deletion of Rb, we used a Cre/loxP system...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.25.6.2486-2497.2005
更新日期:2005-03-01 00:00:00
abstract::Granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates myeloid progenitor cell proliferation and enhances the function of terminally differentiated effector cells. Interleukin-3 (IL-3) stimulation results in the proliferation and maturation of early bone marrow progenitor cells. These activities are medi...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.14.9.5975
更新日期:1994-09-01 00:00:00
abstract::Simple sequence repeat telomeric DNA is maintained by a specialized reverse transcriptase, telomerase. The integral RNA subunit of telomerase contains a template region that determines the sequence added to chromosome ends. Aside from providing the template, little is known about the role of the telomerase RNA. In add...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.19.1.567
更新日期:1999-01-01 00:00:00
abstract::The putative promoter of the variant surface glycoprotein (VSG) gene of Trypanosoma brucei was cloned into a plasmid containing the chloramphenicol acetyltransferase (CAT) gene. After electroporation into trypanosomes, this construct directed the expression of the CAT reporter gene. The essential region for promoter a...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/mcb.11.1.338
更新日期:1991-01-01 00:00:00
abstract::Posttranscriptional regulation is important for tumor necrosis factor alpha (TNF-alpha) expression in monocytes and macrophages, and an AU-rich element (ARE) in the 3' untranslated region (UTR) of TNF-alpha mRNA is implicated in control of its translation and mRNA stability. Regulation of mRNA turnover is thought to b...
journal_title:Molecular and cellular biology
pub_type: 杂志文章
doi:10.1128/MCB.21.3.721-730.2001
更新日期:2001-02-01 00:00:00