14-3-3 proteins integrate E2F activity with the DNA damage response

Milton, Alasdair Hugh; Khaire, Nandkumar; Ingram, L; O’Donnell, Amanda; Thangué, Nicholas B. La

doi:10.1038/sj.emboj.7600999

Cited by 29 publications

(25 citation statements)

References 46 publications

(93 reference statements)

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“…wt, wild type (14-3-3ε ϩ/ϩ ); mut, mutant (14-3-3ε Ϫ/Ϫ ). (35), and knockout of both E cyclins in mice leads to cardiac defects, including VSDs (15). p27 Kip1 -null mice display increased numbers of cardiac myocytes, with fewer cells in the G 0 /G 1 phase (46), findings that are consistent with our results and suggest that increased levels of p27…”

Section: Discussionsupporting

confidence: 90%

“…We cannot rule out the possibility that suppression of the G 2 /M phase at E12.5 (Fig. 4i) results not only from the accumulation of cardiomyocytes in the G 0 /G 1 phase but also from impairment of proteins driving mitosis, such as Cdc25C and Cdk1 (17,35).…”

Section: Discussionmentioning

confidence: 96%

“…It will be important in future investigations to test whether 14-3-3ε regulates the E2F family of transcription factors, because binding of E2F to Rb modulates progression into S phase, and 14-3-3ε regulates E2F (35). We cannot rule out the possibility that suppression of the G 2 /M phase at E12.5 (Fig.…”

Section: Discussionmentioning

confidence: 99%

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14-3-3ε Plays a Role in Cardiac Ventricular Compaction by Regulating the Cardiomyocyte Cell Cycle

Kosaka

Cieslik

et al. 2012

Molecular and Cellular Biology

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f Trabecular myocardium accounts for the majority of the ventricles during early cardiogenesis, but compact myocardium is the primary component at later developmental stages. Elucidation of the genes regulating compact myocardium development is essential to increase our understanding of left ventricular noncompaction (LVNC), a cardiomyopathy characterized by increased ratios of trabecular to compact myocardium. 14-3-3 is an adapter protein expressed in the lateral plate mesoderm, but its in vivo cardiac functions remain to be defined. Here we show that 14-3-3 is expressed in the developing mouse heart as well as in cardiomyocytes. 14-3-3 deletion did not appear to induce compensation by other 14-3-3 isoforms but led to ventricular noncompaction, with features similar to LVNC, resulting from a selective reduction in compact myocardium thickness. Abnormal compaction derived from a 50% decrease in cardiac proliferation as a result of a reduced number of cardiomyocytes in G 2 /M and the accumulation of cardiomyocytes in the G 0 /G 1 phase of the cell cycle. These defects originated from downregulation of cyclin E1 and upregulation of p27 Kip1 , possibly through both transcriptional and posttranslational mechanisms. Our work shows that 14-3-3 regulates cardiogenesis and growth of the compact ventricular myocardium by modulating the cardiomyocyte cell cycle via both cyclin E1 and p27Kip1 . These data are consistent with the long-held view that human LVNC may result from compaction arrest, and they implicate 14-3-3 as a new candidate gene in congenital human cardiomyopathies.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 96%

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14-3-3ε Plays a Role in Cardiac Ventricular Compaction by Regulating the Cardiomyocyte Cell Cycle

Kosaka

Cieslik

et al. 2012

Molecular and Cellular Biology

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“…This suggests that it plays a role in diverse biochemical Heat shock protein 8 activities related to signal transduction, such as cell division, apoptosis and the regulation of insulin sensitivity (28)(29)(30). Studies have suggested that the cleavage of YWHae during apoptosis promotes cell death and induces cell cycle G2 arrest (30); while apoptosis was induced by the expression of e2F, it was less significant in the presence of YWHAE. RRM1, a prb/e2F cell-cycle target gene (31), encodes one of two nonidentical subunits that constitute ribonucleoside-diphosphate reductase, an enzyme essential for the production of deoxyribonucleotides prior to dna synthesis in the S phase of dividing cells.…”

Section: Discussionmentioning

confidence: 99%

Diallyl disulfide inhibits the proliferation of HT-29 human colon cancer cells by inducing differentially expressed genes

Huang

Xie

et al. 2011

Mol Med Rep

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Abstract. diallyl disulfide (dadS), a sulfur compound derived from garlic, has been shown to have protective effects against colon carcinogenesis in several studies performed in rodent models. However, its molecular mechanism of action remains unclear. This study was designed to confirm the antiproliferative activity of dadS and to screen for differentially expressed genes induced by dadS in human colon cancer cells with the aim of exploring its possible anticancer mechanisms. The anti-proliferative capability of dadS in the HT-29 human colon cancer cells was analyzed by MTT assays and flow cytometry. The differences in gene expression between dadStreated (experimental group) and untreated (control group) HT-29 cells were identified using two-directional suppression subtractive hybridization (SSH). Semi-quantitative reverse transcription polymerase chain reaction (semi-rT-Pcr) was selected to confirm the results obtained by SSH. Based on the results, a dose-and time-dependent growth inhibition was observed in the dadS-treated HT-29 cells. Forty-nine known genes and a new gene were found to be involved in the anti-proliferative effects of dadS by SSH analysis, and two cdna libraries, dHdG and dHuG, containing both up-and down-regulated genes in colon tumor cells, were constructed. These genes were related to transduction, cell proliferation/ growth/apoptosis and secreted/extracellular matrix proteins. Semi-rT-Pcr results showed an expression pattern consistent with that of the SSH analysis. in conclusion, dadS showed anti-proliferative effects on colon cancer HT-29 cells, and dHdG and dHuG genes were found to be involved in this process. Further studies on the identification and description of these genes may allow a better understanding of the protective roles of dadS in colon carcinogenesis. Introductioncolon cancer is one of the major causes of cancer death worldwide (1). an understanding of the mechanisms involved in the occurrence and development of colon cancer would aid in its therapy. epidemiological investigations have provided compelling evidence that environmental factors are modifiers in colon cancer (1-3); diet has also been shown to be an important determinant of cancer risk and tumor behavior (3-5).Garlic consumption is very popular all over the world. epidemiological studies have shown an inverse correlation between the consumption of garlic and colon cancer in certain areas (6). Many in vivo experiments have revealed the antitumorigenic activity of garlic or of allyl sulfur compounds from garlic (7-17).Diallyl disulfide (DADS) is the major component of cooked garlic and an oil-soluble organosulfur compound in processed garlic that inhibits the proliferation of several human cancer cells, including breast (11), hepatoma (12), colon cancer (13) and human leukemia . Previous studies from our laboratory revealed that dadS suppresses gastric (15) and colon cancer (16). additionally, leukemia cell proliferation was related to dadS (14,17), possibly because of its ability to induce cell cycle arrest and...

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“…32 The loss of 14-3-3-sigma contributes to tumorigenesis in different tissues including prostate. 33 Compared to DN-ANXA7, WT-ANXA7 upregulated 14-3-3-sigma that was shown to be induced by p53.…”

Section: Anxa7 Protein Affected Cell Viability In Prostate Cancer Celmentioning

confidence: 99%

Annexin‐A7 protects normal prostate cells and induces distinct patterns of RB‐associated cytotoxicity in androgen‐sensitive and ‐resistant prostate cancer cells

Torosyan

Šimáková

Shanmugam

et al. 2009

Intl Journal of Cancer

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The tumor suppressor role of annexin-A7 (ANXA7) was previously demonstrated by cancer susceptibility in Anxa7(1/2)-mice and by ANXA7 loss in human cancers, especially in hormone-resistant prostate tumors. To gain mechanistic insights into ANXA7 tumor suppression, we undertook an in vitro study in which we compared wild-type (WT)-ANXA7 and dominant-negative (DN)-ANXA7 effects to a conventional tumor suppressor p53 in prostate cancer cells with different androgen sensitivity. Unlike p53 (which caused cell growth arrest and apoptosis to a noticeable extent in benign PrEC), WT-ANXA7 demonstrated profound cytotoxicity in androgen-sensitive LNCaP as well as in the androgen-resistant DU145 and PC3 prostate cancer cells, but not in PrEC. In androgen-sensitive LNCaP, WT-ANXA7 decreased lowmolecular-weight (LMW) AR protein forms and maintained higher retinoblastoma 1 (RB1)/phospho-RB1 ratio. In contrast, DN-ANXA7 (which lacks phosphatidylserine liposome aggregation properties) increased LMW-AR forms and hyperphosphorylated RB1 that was consistent with the lack of DN-ANXA7 cytotoxicity. According to the microarray-based Ingenuity Pathways Analysis, a major WT-ANXA7 effect in androgen-sensitive LNCaP constituted of upregulation of the RB1-binding transcription factor E2F1 along with its downstream proapoptotic targets such as ASK1 and ASPP2. These results suggested a reversal of the RBdependent repression of the proapoptotic E2F-mediated transcription. However, DN-ANXA7 increased RB1/2 (but not E2F1) expression and induced the proliferation-promoting ERK5, thereby maintaining the RB-dependent repression of E2F-mediated apoptosis in LNcaP. On the other hand, in androgen-resistant cells, WT-ANXA7 tumor suppressor effects involved PTEN and NFkB pathways. Thus, ANXA7 revived the RB-associated cell survival control and overcame androgen resistance and dysfunctional status of major tumor suppressors commonly mutated in prostate cancer. Published 2009 UICC. This article is a US Government work and, as such, is in the public domain in the United States of America.Key words: annexin-A7 vs. p53; RB-E2F; AR; prostate cancer; Ingenuity Pathways Analysis Annexin-VII (ANXA7 or synexin) is a ubiquitously expressed member of the multifunctional Ca/phospholipid-binding annexin family. In addition to Ca 21 -activated GTPase activity as well as involvement in membrane fusion and exocytosis, ANXA7 demonstrated tumor suppressor function in murine model 1 and in human prostate and breast cancers. 2,3 Our large-scale study on ANXA7 protein expression in different cancers 4 identified a drastic ANXA7 loss in the hormone-refractory prostate cancers as well as an abundant ANXA7 presence in the adrenal gland, a major source of sex hormone precursors. Although tumor suppressor mechanisms of ANXA7 are not yet elucidated, these data suggested that ANXA7, which has androgen-receptor (AR) regulatory elements in its promoter, may be involved in the regulation of androgen-dependent cell survival in prostate cancer cells.Androgen-dependent proliferation is p...

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14-3-3 proteins integrate E2F activity with the DNA damage response

Cited by 29 publications

References 46 publications

14-3-3ε Plays a Role in Cardiac Ventricular Compaction by Regulating the Cardiomyocyte Cell Cycle

14-3-3ε Plays a Role in Cardiac Ventricular Compaction by Regulating the Cardiomyocyte Cell Cycle

Diallyl disulfide inhibits the proliferation of HT-29 human colon cancer cells by inducing differentially expressed genes

Annexin‐A7 protects normal prostate cells and induces distinct patterns of RB‐associated cytotoxicity in androgen‐sensitive and ‐resistant prostate cancer cells

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