The Rb Gene Suppresses the Growth of Normal Cells

Fung, Y. K.; Tang, Anzhou; Murphree, A. Linn; Zhang, F. H.; Qiu, Wenbing; Wang, S. W.; Xu, Shichao; Lee, L.; Driscoll, Barbara; Wu, Kuen-Yuh

doi:10.1097/00006982-199401000-00031

Cited by 10 publications

(11 citation statements)

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“…To confirm that Rb negatively regulates Myc expression through this E2F site in cardiac myocytes, neonatal myocytes were transfected with the Myc promoter along with wild-type Rb or Rb-p16, an inactive mutant that is unable to bind E2F or suppress growth (14) (Fig. 7B).…”

Section: Resultsmentioning

confidence: 99%

Overlapping Roles of Pocket Proteins in the Myocardium Are Unmasked by Germ Line Deletion of p130 plus Heart-Specific Deletion of Rb

MacLellan

Garcia

et al. 2005

Molecular and Cellular Biology

115

104

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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 to create conditional, heart-specific Rb-deficient mice. Mice that are deficient in Rb exclusively in cardiac myocytes (CRb L/L ) are born with the expected Mendelian distribution, and the adult mice displayed no change in heart size, myocyte cell cycle distribution, myocyte apoptosis, or mechanical function. Since both Rb and p130 are expressed in the adult myocardium, we created double-knockout mice (CRb L/L p130 ؊/؊ ) to determine it these proteins have a shared role in regulating cardiac myocyte cell cycle progression. Adult CRb L/L p130 ؊/؊ mice demonstrated a threefold increase in the heart weight-to-body weight ratio and showed increased numbers of bromodeoxyuridine-and phosphorylated histone H3-positive nuclei, consistent with persistent myocyte cycling. Likewise, the combined deletion of Rb plus p130 up-regulated myocardial expression of Myc, E2F-1, and G 1 cyclin-dependent kinase activities, synergistically. Thus, Rb and p130 have overlapping functional roles in vivo to suppress cell cycle activators, including Myc, and maintain quiescence in postnatal cardiac muscle.

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Section: Resultsmentioning

confidence: 99%

Overlapping Roles of Pocket Proteins in the Myocardium Are Unmasked by Germ Line Deletion of p130 plus Heart-Specific Deletion of Rb

MacLellan

Garcia

et al. 2005

Molecular and Cellular Biology

115

104

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“…C/EBP⑀ and C/EBP␣ expression were induced by adding ZnSO 4 (100 M) to the medium. Transient transfections were performed with various expression vectors (C/EBP⑀, 24 Rb, 25 and E2F1 26 ) or a control empty vector (pcDNA3; Invitrogen, Carlsbad, CA) using the GenePORTER transfection reagent.…”

Section: Cell Culture and Transfectionsmentioning

confidence: 99%

“…A deletion mutant encoding only the repression domain of C/EBP⑀ (aa's 103-193) failed to bind Rb. The N-terminal portion of C/EBP⑀ contains a sequence (aa's to [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27]) that may be involved in the C/EBP⑀-Rb interaction because it is similar to a sequence used by E2F1 to interact with Rb 28 ( Figure 2B). Similar sequences also are found in C/EBP␣, C/EBP␤, and C/EBP␦.…”

Section: Org Frommentioning

confidence: 99%

C/EBPϵ interacts with retinoblastoma and E2F1 during granulopoiesis

Gery

Gombart

Fung

et al. 2004

Blood

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CCAAT enhancer binding protein epsilon (C/EBP⑀) is a myeloid specific transcription factor that is essential for terminal granulocytic differentiation. Retinoblastoma (Rb) and E2F1 are critical cell cycle regulators that also have been implicated in several differentiation systems. Here, we demonstrate that C/EBP⑀ interacts with Rb and E2F1 during granulocytic differentiation in NB4 and U937 human myeloid cells and in 32Dcl3 murine myeloid precursor cells. The interaction between C/EBP⑀ and Rb enhances C/EBP⑀-mediated transcription of myeloid specific genes both in reporter assays and endogenously. The C/EBP⑀-E2F1 interaction results in repression of E2F1-mediated transcriptional activity. Finally, overexpression of C/EBP⑀ in human myeloid cells leads to down-regulation of c-Myc.We propose that the interactions between C/EBP⑀, a tissue-specific transcription factor, and the broad-spectrum proteins, Rb and E2F1, are important in C/EBP⑀-induced terminal granulocytic differentiation. ( IntroductionIn hematopoiesis, stem cells generate mature blood cells of specific lineages, in a process that is tightly regulated by transcription factors. CCAAT enhancer binding protein epsilon (C/EBP⑀) is a member of the C/EBP family of transcription factors that share a highly conserved basic region and a leucine zipper domain (bZIP). 1 C/EBP⑀ is expressed almost exclusively in myeloid cells and activates the transcription of a subset of myeloid specific genes. 2,3 Mice and humans with genetic deletion of C/EBP⑀ have a block in granulocytic differentiation and often have either severe or fatal chronic bacterial infections. [4][5][6] Likewise, induction of neutrophil differentiation in promyelocytic leukemia lines is associated with C/EBP⑀ expression, and forced expression of C/EBP⑀ in these cells can induce granulocytic differentiation. [7][8][9] These findings indicate that C/EBP⑀ is a critical regulator of terminal granulopoiesis.Recent studies have emphasized the important role that proteinprotein interactions play in the ability of C/EBPs to regulate differentiation and cell growth. 10 Interestingly, 2 key regulators of the cell cycle, retinoblastoma (Rb) and E2F1, have been linked to differentiation and growth suppression events that are mediated by members of the C/EBP family. The tumor suppressor gene Rb has a well-established role in the regulation of cell cycle progression. 11 In G1, hypophosphorylated Rb sequesters the E2F transcription factors whose target genes are necessary for the G1/S transition. In recent years, evidence has been accumulating that Rb also is involved in cellular differentiation. 12,13 Transgenic mice with inactivated Rb show defective differentiation of hematopoietic and neuronal tissues and die after 14 to 15 days of gestation. [14][15][16] In addition, hypophosphorylation of Rb correlates with the differentiation of normal and leukemic hematopoietic cells in vitro. 17,18 Rb binds and activates C/EBP␤, and this interaction has been found to be involved in differentiation of adipocytes and monocyt...

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“…The plasmids Hu~Acpr-l-neo-PQ (herein referred as p[3Actvector) and its RB derivative (p~ActRB) were obtained from Y.-K. T. Fung [Childrens Hospital Los Angeles, CA (Fung et al 1993)]. The plasmid pSP72-E2F1, expressing E2F-1 mRNA from a SP6 promoter, was obtained from W.G.…”

Section: Plasmidsmentioning

confidence: 99%

The helix-loop-helix protein Id-2 enhances cell proliferation and binds to the retinoblastoma protein.

Iavarone¹,

Garg²,

Lasorella³

et al. 1994

Genes Dev.

338

313

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Cell growth and differentiation are usually antagonistic. Proteins of the basic helix-loop-helix (bHLH) family bind DNA and play important roles in the differentiation of specific cell types. Id proteins heterodimerize with bHLH transcription factors, blocking their activation of lineage-specific gene expression and thereby inhibiting cellular differentiation. To examine the effect of Id-2 on cell proliferation, we overexpressed Id-2 in the human osteosarcoma cell line U2OS. Id-2 expression in U2OS reduced the serum requirement for growth and stimulated cellular proliferation by shortening the doubling time and increasing the percentage of cells in S phase. We demonstrated that Id-2 expression was able to reverse the inhibition of cellular proliferation and the block in cell cycle progression mediated by the product of the retinoblastoma tumor suppressor gene pRB. This effect was not associated with changes in the state of pRb phosphorylation in transfected cells. In vitro, unphosphorylated pRb from cell lysates specifically bound Id-2 but was not able to bind a mutated form of Id-2 lacking the HLH domain that also did not antagonize the growth arrest by pRb. In vitro-synthesized pRb containing mutations within the E1A/large T-binding pocket did not bind Id-2. However, wild-type pRb was able to bind to a region of Id-2 corresponding to only the HLH domain. In vivo, a physical association between Id-2 and pRb was seen in cross-linked extracts from SAOS-2 cells transfected with Id-2 and pRb. Our data identify a role for Id-2 in the regulation of cellular proliferation and suggest that the interaction between Id-2 and pRb is a molecular pathway over which synchronous changes in growth and differentiation are mediated in vivo.

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The Rb Gene Suppresses the Growth of Normal Cells

Cited by 10 publications

References 0 publications

Overlapping Roles of Pocket Proteins in the Myocardium Are Unmasked by Germ Line Deletion of p130 plus Heart-Specific Deletion of Rb

Overlapping Roles of Pocket Proteins in the Myocardium Are Unmasked by Germ Line Deletion of p130 plus Heart-Specific Deletion of Rb

C/EBPϵ interacts with retinoblastoma and E2F1 during granulopoiesis

The helix-loop-helix protein Id-2 enhances cell proliferation and binds to the retinoblastoma protein.

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