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429
Id2 specifically alters regulation of the cell cycle by tumor suppressor proteins
, 1996
"... Cells which are highly proliferative typically lack expression of differentiated, lineage-specific characteristics. Id2, a member of the helix-loop-helix (HLH) protein family known to inhibit cell differentiation, binds to the retinoblastoma protein (pRb) and abolishes its growth-suppressing activit ..."
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Cells which are highly proliferative typically lack expression of differentiated, lineage-specific characteristics. Id2, a member of the helix-loop-helix (HLH) protein family known to inhibit cell differentiation, binds to the retinoblastoma protein (pRb) and abolishes its growth-suppressing activity. We found that Id2 but not Id1 or Id3 was able to bind in vitro not only pRb but also the related proteins p107 and p130. Also, an association between Id2 and p107 or p130 was observed in vivo in transiently transfected Saos-2 cells. In agreement with these results, expression of Id1 or Id3 did not affect the block of cell cycle progression mediated by pRb. Conversely, expression of Id2 specifically reversed the cell cycle arrest induced by each of the three members of the pRb family. Furthermore, the growth-suppressive activities of cyclin-dependent kinase inhibitors p16 and p21 were efficiently antagonized by high levels of Id2 but not by Id1 or Id3. Consistent with the role of p16 as a selective inhibitor of pRb and pRb-related protein kinase activity, p16-imposed cell cycle arrest was completely abolished by Id2. Only a partial reversal of p21-induced growth suppression was observed, which correlated with the presence of a functional pRb. We also documented decreased levels of cyclin D1 protein and mRNA and the loss of cyclin D1-cdk4 complexes in cells constitutively expressing Id2. These data provide evidence for important Id2-mediated alterations in cell cycle components normally involved in the regulatory events of cell cycle progression, and they highlight a specific role for Id2 as an antagonist of multiple tumor
Interaction between the human cytomegalovirus UL82 gene product (pp71) and hDaxx regulates immediateearly gene expression and viral replication
- J
, 2005
"... The human cytomegalovirus UL82-encoded pp71 protein is required for efficient virus replication and immediate-early gene expression when cells are infected at a low multiplicity. Functions attributed to pp71 include the ability to enhance the infectivity of viral DNA, bind to and target hypophosphor ..."
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The human cytomegalovirus UL82-encoded pp71 protein is required for efficient virus replication and immediate-early gene expression when cells are infected at a low multiplicity. Functions attributed to pp71 include the ability to enhance the infectivity of viral DNA, bind to and target hypophosphorylated Rb family member proteins for degradation, drive quiescent cells into the cell cycle, and bind to the cellular protein hDaxx. Using UL82 mutant viruses, we demonstrate that the LXCXD motif within pp71 is not necessary for efficient virus replication in fibroblasts, suggesting that pp71’s ability to degrade hypophosphorylated Rb family members and induce quiescent cells into the cell cycle is not responsible for the growth defect associated with a UL82 deletion mutant. However, UL82 mutants that cannot bind to hDaxx are unable to induce immediate-early gene expression and are severely attenuated for viral replication. These results indicate that the interaction between the human cytomegalovirus UL82 gene product (pp71) and hDaxx regulates immedi-ate-early gene expression and viral replication. Human cytomegalovirus (HCMV) is a ubiquitous human pathogen. Although HCMV infection is usually asymptomatic in healthy individuals, HCMV infection can result in severe disease in newborns infected in utero and in immunocompro-
Glucocorticoid receptor-mediated cell cycle arrest is achieved through distinct cell-specific transcriptional regulatory mechanisms
, 1997
"... Glucocorticoid receptor-mediated cell cycle arrest is achieved through distinct cell-specific transcriptional regulatory mechanisms. ..."
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Cited by 25 (1 self)
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Glucocorticoid receptor-mediated cell cycle arrest is achieved through distinct cell-specific transcriptional regulatory mechanisms.
2002. T antigens of simian virus 40: molecular chaperones for viral replication and tumorigenesis
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Noninvasive imaging of spontaneous retinoblastoma pathway-dependent tumors in mice
- Cancer Res
, 2002
"... Identification of the critical pathways involved in tumorigenesis should ultimately lead to the design of better anticancer agents that target specific components of the disrupted pathways. Murine models of spontaneous cancer in which tumor formation is dependent on defined genetic alter-ations prov ..."
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Cited by 23 (0 self)
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Identification of the critical pathways involved in tumorigenesis should ultimately lead to the design of better anticancer agents that target specific components of the disrupted pathways. Murine models of spontaneous cancer in which tumor formation is dependent on defined genetic alter-ations provide a powerful test system for evaluating the therapeutic efficacy of pathway-specific antineoplastics. We have generated a condi-tional mouse model for retinoblastoma-dependent sporadic cancer that permits noninvasive monitoring of pituitary tumor development in live animals via in vivo bioluminescence imaging of luciferase expression. We show that the high sensitivity of bioluminescence imaging can be used for noninvasive detection of luciferase expression in pituitary glands from tumor-free animals and for in vivo quantitation of tumor burden over a large dynamic range. This mouse model permits longitudinal monitoring of tumor onset, progression, and response to therapy and may be used effectively for testing cancer prevention and treatment strategies based on therapeutics that specifically target the retinoblastoma pathway.
Human cytomegalovirus IE2 86-kilodalton protein binds p53 but does not abrogate G1 checkpoint function
- J
, 1997
"... Physical interactions between human cytomegalovirus (HCMV) immediate-early (IE) proteins and key cell cycle regulatory proteins have been suggested as a mechanism whereby this herpesvirus modifies cellular control of proliferation. Observed similarities to interactions of other DNA virus proteins (h ..."
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Cited by 22 (0 self)
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Physical interactions between human cytomegalovirus (HCMV) immediate-early (IE) proteins and key cell cycle regulatory proteins have been suggested as a mechanism whereby this herpesvirus modifies cellular control of proliferation. Observed similarities to interactions of other DNA virus proteins (human papilloma-virus type 16 E6 and E7, simian virus 40 large T antigen, and adenovirus type 5 E1A and E1B) with cell cycle modulatory proteins such as p53 and Rb have suggested that HCMV IE proteins may likewise alter the G1-to-S phase transition. The IE2 region gene product IE86 has been shown to specifically bind p53, potentially modifying p53 G1 checkpoint function. To examine this possibility, p53-mediated G1 arrest in the presence of IE86 was assessed. Retroviral constructs were created to facilitate the stable expression of IE86 and IE72, another IE protein implicated in HCMV-mediated alteration of cell cycle progression. Western analysis and immunoprecipitation confirmed IE protein expression and binding of IE86 to p53, respectively. Chloramphen-icol acetyltransferase assays examining the ability of IE86 to repress activity from the HCMV major IE promoter or activate the HCMV early promoter for the 2.2-kb class of RNAs demonstrated the functional integrity of the IE86 protein. Induction of DNA damage in normal, uninfected fibroblasts (FB) or FB express-ing IE86 by actinomycin D (Act D) resulted in increased p53 levels, a predominance of the hypophosphorylated form of Rb, and increased expression of both p21CIP1/WAF1 and mdm-2. Fluorescence-activated cell sorting
Meloche S: Differential regulation of p27 kip1 expression by mitogenic and hypertrophic factors: Involvement of transcriptional and posttranscriptional mechanisms
- J Cell Biol
"... Abstract. Platelet-derived growth factor-BB (PDGF-BB) acts as a full mitogen for cultured aortic smooth muscle cells (SMC), promoting DNA synthesis and cell proliferation. In contrast, angiotensin II (Ang II) induces cellular hypertrophy as a result of increased protein synthesis, but is unable to d ..."
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Abstract. Platelet-derived growth factor-BB (PDGF-BB) acts as a full mitogen for cultured aortic smooth muscle cells (SMC), promoting DNA synthesis and cell proliferation. In contrast, angiotensin II (Ang II) induces cellular hypertrophy as a result of increased protein synthesis, but is unable to drive cells into S phase. In an effort to understand the molecular basis for this differential growth response, we have examined the downstream effects of PDGF-BB and Ang II on regulators of the cell cycle machinery in rat aortic SMC. Both PDGF-BB and Ang II were found to stimulate the accumulation of G 1 cyclins with similar kinetics. In addition, little difference was observed in the expression level of their catalytic partners, Cdk4 and Cdk2. However, while both factors increased the enzymatic activity of Cdk4, only PDGF-BB stimulated Cdk2 activity in late G 1 phase. The lack of activation of Cdk2 in Ang IItreated cells was causally related to the failure of Ang II to stimulate phosphorylation of the enzyme on threonine and to downregulate p27 Kip1 expression. By contrast, exposure to PDGF-BB resulted in a progressive and dramatic reduction in the level of p27 Kip1 protein. The time course of p27 Kip1 decline was correlated with a reduced rate of synthesis and an increased rate of degradation of the protein. Importantly, the repression of p27 Kip1 synthesis by PDGF-BB was associated with a marked attenuation of Kip1 gene transcription and a corresponding decrease in Kip1 mRNA accumulation. We also show that the failure of Ang II to promote S phase entry is not related to the autocrine production of transforming growth factor-�1 by aortic SMC. These results identify p27 Kip1 as an important regulator of the phenotypic response of vascular SMC to mitogenic and hypertrophic stimuli. Key words: growth factors • cell cycle • CDK inhibitors • gene expression • smooth muscle cells
Altered cell cycle kinetics, gene expression, and G1 restriction point regulation in Rb-deficient fibroblasts
- Mol. Cell. Biol
, 1996
"... Fibroblasts prepared from retinoblastoma (Rb) gene-negative mouse embryos exhibit a shorter G1 phase of the growth cycle and smaller size than wild-type cells. In addition, the mutant cells are no longer inhibited by low levels of cycloheximide at any point in G1 but do remain sensitive to serum wit ..."
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Fibroblasts prepared from retinoblastoma (Rb) gene-negative mouse embryos exhibit a shorter G1 phase of the growth cycle and smaller size than wild-type cells. In addition, the mutant cells are no longer inhibited by low levels of cycloheximide at any point in G1 but do remain sensitive to serum withdrawal until late in G1. Certain cell cycle-regulated genes showed no temporal or quantitative differences in expression. In contrast, cyclin E expression in Rb-deficient cells is deregulated in two ways. Cyclin E mRNA is generally derepressed in mutant cells and reaches peak levels about 6 h earlier in G1 than in wild-type cells. Moreover, cyclin E protein levels are higher in the Rb2/2 cells than would be predicted from the levels of its mRNA. Thus, the selective growth advantage conferred by Rb gene deletion during tumorigenesis may be explained in part by changes in the regulation of cyclin E. In addition, the mechanisms defining the restriction point of late G1 may consist of at least two molecular events, one cycloheximide sensitive and pRb dependent and the other serum sensitive and pRb independent. The retinoblastoma (Rb) tumor suppressor gene is inacti-vated in a wide range of human tumors. Its encoded protein, pRb, has been implicated in cell cycle regulation and is known to regulate members of the E2F family of transcription factors.
A conserved family of WD-40 proteins binds to the retinoblastoma protein in both plants and animals. Plant Cell 9:1595–1606
, 1997
"... In mammalian cells, the retinoblastoma (RB) protein regulates G, progression and functions through its association with various cellular proteins. Two closely related mammalian RB binding proteins, RbAp48 and RbAp46, share sequence homology with the Msil protein of yeast. MSll is a multicopy suppres ..."
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In mammalian cells, the retinoblastoma (RB) protein regulates G, progression and functions through its association with various cellular proteins. Two closely related mammalian RB binding proteins, RbAp48 and RbAp46, share sequence homology with the Msil protein of yeast. MSll is a multicopy suppressor of a mutation in the lRA1jgene involved in the Ras-cAMP pathway that regulates cellular growth. Human RbAp48 is present in protein complexes involved in histone acetylation and chromatin assembly. We report the cloning of cDNAs encoding four plant RbAp48and Msil-like proteins: one from tomato, LeMSIf, and three from Arabidopsis. Complementation studies confirm that LeMSl7 can function as a multicopy suppressor of the yeast ira1 mutant phenotype. The LeMSI1 protein localizes to the nucleus and binds to a 65-kD protein in wild-type as well as ripening inhibitor (rin) and Neverripe (Nr) tomato fruit. LeMSll also binds to the human RB protein and the RB-like RRBl protein from maize, indicating that this interaction is conserved between plants and animals.
Down-regulation of cyclin D1 expression by prostaglandin A 2 is mediated by enhanced cyclin D1 mRNA
, 2000
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Cited by 20 (11 self)
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