Evolutionarily Conserved Multisubunit RBL2/p130 and E2F4 Protein Complex Represses Human Cell Cycle-Dependent Genes in Quiescence

Litovchick, Larisa; Sadasivam, Subhashini; Florens, Laurence; Zhu, Xiaopeng; Swanson, Selene K.; Velmurugan, Soundarapandian; Chen, Runsheng; Washburn, Michael P.; Liu, X. Shirley; DeCaprio, James A.

doi:10.1016/j.molcel.2007.04.015

Cited by 361 publications

(765 citation statements)

References 39 publications

(74 reference statements)

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“…Cancer cells could elevate their expression of ILK in response to TWIST depletion, which could help to compensate for the effects of loss of TWIST expression. RBL2 is a member of the retinoblastoma family of proteins, which represses E2F target genes and controls cell proliferation, differentiation, and transformation by inducing cell cycle arrest (Litovchick et al, 2007). Up-regulation of RBL2 was found after TWIST depletion in our study, suggesting a possible mechanism whereby TWIST may promote cell proliferation by transcriptional repression of RBL2.…”

Section: Discussionsupporting

confidence: 49%

Gene Expression Profiling in TWIST‐Depleted Gastric Cancer Cells

Feng

Wang

Shi

et al. 2008

The Anatomical Record

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TWIST is an important transcription factor during embryonic development and has recently been found to promote the epithelial-mesenchymal transition (EMT) phenomenon seen during the initial steps of tumor metastasis. To further investigate the potential targets and interacting genes of TWIST in human gastric cancer, we performed microarray analysis to compare the gene expression profiles in HGC-27 cells, with or without small interfering RNA (siRNA)-mediated depletion of TWIST. Our results showed that NF1, RAP1A, SRPX, RBL2, PFDN4, ILK, F2R, ERBB3, and MYB were up-regulated, whereas AKR1C2, FOS, GDF15, NR2F1, ATM, and CTPS were down-regulated after TWIST depletion. Moreover, TWIST-depleted HGC-27 cells showed a reversal of the morphologic and molecular changes associated with EMT. These results provide evidence that TWIST regulates the expression of several genes involved in the differentiation, adhesion, and proliferation of gastric cancer cells. The role of TWIST in the development of certain types of gastric cancer is discussed. Anat Rec, 292:262-270, 2009Rec, 292:262-270, . 2008 Wiley-Liss, Inc.Key words: TWIST; siRNA; epithelial-mesenchymal transition; gastric cancer; microarray Epithelial-mesenchymal transition (EMT) is pivotal for morphogenesis and in the transformation of early stage tumors into invasive malignancies (Kang and Massague, 2004). Cells undergoing EMT-characterized by the loss of cell polarity, cell-basement membrane adhesion, and cell-cell contacts-lose expression of epithelial markers (such as E-cadherin and catenin) and acquire expression of mesenchymal components (such as vimentin, fibronectin, and N-cadherin). Recent studies have shown that TWIST is one of the main regulatory proteins that promote EMT and the metastatic phenotype of cells (Karreth and Tuveson, 2004). Increased levels of TWIST are found in a wide range of cancers and are positively correlated with tumor aggressiveness and poor survival rates (Yang et al., 2004), suggesting a general role for TWIST in cancer development.TWIST is a basic helix-loop-helix (bHLH) transcription regulator that can form homodimers or heterodimers with partners that also contain an HLH domain. Depending on the protein partners in the dimers, these complexes play distinct roles in regulating the expression of downstream genes, acting either as activators or repressors. For example, TWIST homodimers can bind to the E-box of the E-cadherin promoter, repressing its expression, whereas their binding to the E-box of the Akt2 gene enhances its expression (Cheng et al

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Section: Discussionsupporting

confidence: 49%

Gene Expression Profiling in TWIST‐Depleted Gastric Cancer Cells

Feng

Wang

Shi

et al. 2008

The Anatomical Record

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“…Significantly, this system permits analysis of LINC function in gene activation without the confounding background of gene repression mediated by LINC complexes with E2F4 and the pocket proteins p130 and p107 (the dREAM complex). Some previous results suggest that LINC proteins were enriched only on genes upregulated at G 1 /S through interaction with p130/ E2F4 and p107/E2F complexes (Litovchick et al, 2007), and that the primary function of these complexes is to repress transcription of cell-cycle genes in G 0 /G 1 . It was also suggested that B-Myb activated Cdc2 and Cyclin B1 transcription during G 2 through replacement of repressive E2F complexes with activating E2Fs (Zhu et al, 2004).…”

Section: Discussionmentioning

confidence: 95%

“…Caenorhabditis elegans contains the DRM complex (Harrison et al, 2006) and three reports have identified human complexes, named LINC (or DREAM), whose composition is regulated at distinct phases of the cell cycle (Litovchick et al, 2007;Schmit et al, 2007;Pilkinton et al, 2007a). LINC contains Lin-9, Lin-37, Lin-54, Lin-52 and RbAp48 (the human homologues of Drosophila Mip130, Mip40, Mip120, dLin-52 and Caf1p55, respectively).…”

Section: Introductionmentioning

confidence: 99%

“…LINC contains Lin-9, Lin-37, Lin-54, Lin-52 and RbAp48 (the human homologues of Drosophila Mip130, Mip40, Mip120, dLin-52 and Caf1p55, respectively). In G 0 -G 1 , LINC binds to E2F4 and either p130 or p107 to repress transcription of E2F target genes regulating the G 1 /S transition (Litovchick et al, 2007). In S-G 2 , LINC switches to B-Myb to activate genes required for G 2 /M transition and mitosis (Schmit et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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A Lin-9 complex is recruited by B-Myb to activate transcription of G2/M genes in undifferentiated embryonal carcinoma cells

2009

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It has recently been discovered that cell-cycle gene transcription is regulated by a core complex named LINC that switches from a transcriptionally repressive complex in G 0 -G 1 with the p130 or p107 pocket proteins and E2F4 to a transcriptionally active complex in S-G 2 containing B-Myb. We have studied the function of LINC in F9 embryonal carcinoma cells, which are distinguished by a rapid cell cycle resulting from an extremely short G 1 phase. We show that suppressing expression of the LINC component, Lin-9, in F9 cells causes arrest in mitosis, and we have used this system to screen for transcriptional targets. In these cells, B-Myb was found in complexes with Lin-9 and several other LINC constituents, however, the pocket proteins did not associate with LINC unless F9 cells were differentiated. Lin-9 and B-Myb were both required for transcription of G 2 /M genes such as Cyclin B1 and Survivin. Moreover, B-Myb was demonstrated to recruit Lin-9 to the Survivin promoter through multiple Myb-binding sites. The demonstration that a B-Myb/ LINC complex is vital for progression through mitosis in cells lacking a G 1 /S checkpoint has implications for both undifferentiated embryonal cells and for cancers in which pocket protein function is compromised.

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“…The DREAM (or LINC) complex is a master regulator of mitotic gene expression during the cell cycle (Schmit et al, 2007, reviewed in Blais and Dynlacht, 2007;Litovchick et al, 2007;Osterloh et al, 2007;Pilkinton et al, 2007a;Knight et al, 2009). Several proteins that are involved in chromosome segregation and cytokinesis, such as Bub1 and survivin, are direct targets of DREAM (Osterloh et al, 2007;Schmit et al, 2007;Pilkinton et al, 2007b;Knight et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Loss of LIN9, a member of the DREAM complex, cooperates with SV40 large T antigen to induce genomic instability and anchorage-independent growth

et al. 2011

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The DREAM complex is an important regulator of mitotic gene expression during the cell cycle. Here we report that inactivation of LIN9, a subunit of DREAM, results in premature senescence, which can be overcome by the SV40 large T (LT) antigen. Together with the observation that p16 INK4a and p21 Waf1 are upregulated upon loss of LIN9, these results indicate that senescence is triggered by the pRB and p53 tumor suppressor pathways. We also find that LIN9-null cells that escape senescence are chromosomally instable because of compromised mitotic fidelity. SV40 LT-expressing cells that adapt to the loss of LIN9 can grow anchorage-independently in soft agar, a hallmark of oncogenic transformation. Taken together, these results suggest an important role of mitotic gene regulation in the maintenance of genomic stability and tumor suppression.

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Evolutionarily Conserved Multisubunit RBL2/p130 and E2F4 Protein Complex Represses Human Cell Cycle-Dependent Genes in Quiescence

Cited by 361 publications

References 39 publications

Gene Expression Profiling in TWIST‐Depleted Gastric Cancer Cells

Gene Expression Profiling in TWIST‐Depleted Gastric Cancer Cells

A Lin-9 complex is recruited by B-Myb to activate transcription of G2/M genes in undifferentiated embryonal carcinoma cells

Loss of LIN9, a member of the DREAM complex, cooperates with SV40 large T antigen to induce genomic instability and anchorage-independent growth

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