Forkhead box proteins: tuning forks for transcriptional harmony

Lam, Eric W.‐F.; Brosens, Jan J.; Gomes, Ana; Koo, Chuay-Yeng

doi:10.1038/nrc3539

Cited by 599 publications

(622 citation statements)

References 191 publications

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“…The G 2 -M arrest observed can be because of the fact that FOXO3a negatively regulates the expression of genes, including cyclin B and FOXM1 ( Fig. 1A) important for G 2 -M progression (2,36). Collectively, these data suggest that dexamethasone arrests cell-cycle progression, particularly in G 2 -M phase, and induces cell death in the sensitive but not resistant B-ALL cells.…”

Section: Discussionmentioning

confidence: 67%

“…It is well-established that Akt (PKB)-mediated phosphorylation and inactivation of FOXO3a culminate in cytoplasmic localization and cell proliferation (2,3). Herein, we showed that in the sensitive B-ALL cell lines, RS4,11 and SUP-B15, FOXO3a became dephosphorylated on Akt-targeted sites, Ser253, Thr315, and Thr32 upon dexamethasone treatment, but its phosphorylation was unaffected by dexamethasone in the resistant REH cells.…”

Section: Discussionmentioning

confidence: 73%

“…Ã , significant P < 0.05; ÃÃ , very significant P < 0.01; no marker, not significant. phase transition, including cyclin B, Aurora B, and FOXM1 (2), and this may explain the G 2 -M arrest observed after FOXO3a induction by dexamethasone. Besides protein-coding genes, FOXO3a might also regulate the expression of non-proteincoding RNAs to modulate dexamethasone response.…”

Section: Discussionmentioning

confidence: 99%

“…FOXO3a (previously known as FKHR-L1) is a member of the Forkhead family of transcription factors, which share a distinct forkhead DNA-binding domain (2). FOXO3a plays an important role in proliferation, apoptosis, autophagy, metabolism, inflammation, differentiation, and stress resistance (3,4).…”

Section: Introductionmentioning

confidence: 99%

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FOXO3a and Posttranslational Modifications Mediate Glucocorticoid Sensitivity in B-ALL

Consolaro

Ghaem‐Maghami

Bortolozzi

et al. 2015

Molecular Cancer Research

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Glucocorticoids are widely used to treat B acute lymphoblastic leukemia (B-ALL); however, the molecular mechanism underlying glucocorticoid response and resistance is unclear. In this study, the role and regulation of FOXO3a in mediating the dexamethasone response in B-ALL were investigated. The results show that FOXO3a mediates the cytotoxic function of dexamethasone. In response to dexamethasone, it was found that FOXO3a translocates into the nucleus, where it induces the expression of downstream targets, including p27Kip1 and Bim, important for proliferative arrest and cell death in the sensitive RS4;11 and SUP-B15 B-ALL cells. FOXO3a activation by dexamethasone is mediated partially through the suppression of the PI3K/Akt signaling cascade. Furthermore, two posttranslational modifications were uncovered, phosphorylation on Ser-7 and acetylation on Lys-242/5, that associated with FOXO3a activation by dexamethasone. Immunoblot analysis showed that the phosphorylation on Ser-7 of FOXO3a is associated with p38/ JNK activation, whereas the acetylation on Lys-242/5 is correlated with the downregulation of SIRT1/2/6 and the induction of the acetyltransferase CBP/p300. Collectively, these results indicate that FOXO3a is essential for dexamethasone response in B-ALL cells, and its nuclear translocation and activation is associated with its phosphorylation on Ser-7 and acetylation on Lys-242/245. These posttranslational events can be exploited as biomarkers for B-ALL diagnosis and as drug targets for B-ALL treatment, particularly for overcoming the glucocorticoid resistance.Implications: FOXO3a and its posttranslational regulation are essential for dexamethasone response, and targeting FOXO3a and sirtuins may enhance the dexamethasone-induced cytotoxicity in B-ALL cells.

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

FOXO3a and Posttranslational Modifications Mediate Glucocorticoid Sensitivity in B-ALL

Consolaro

Ghaem‐Maghami

Bortolozzi

et al. 2015

Molecular Cancer Research

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“…Recent whole genome analysis identified a GATA3 mutation which exists in 14% of luminal A breast cancer [35]. It was reported that ERα, FOXA1 and GATA3 form a functional enhanceosome to drive the transcription of ERα-regulated genes in breast cancer cells [36,37]. High FOXA1 and GATA3 expression might therefore affect endocrine responsiveness and prognosis in ER-positive breast cancer [38].…”

Section: Discussionmentioning

confidence: 99%

Differential expression of progesterone receptor, FOXA1, GATA3, and p53 between pre- and postmenopausal women with estrogen receptor-positive breast cancer

Hosoda

Yamamoto

Nakano

et al. 2014

Breast Cancer Res Treat

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Estrogen receptor (ER) is essential for estrogen-dependent growth, and its level of expression is considered a crucial determinant of response to endocrine therapy and prognosis in ER-positive breast cancer. On the other hand, the clinical role of progesterone receptor (PgR) in ER-positive breast cancer remains controversial, although testing of PgR by immunohistochemistry (IHC) has become routine. Recent studies indicated that plasma estradiol levels were related to expression levels of estrogen-responsive genes in ER-positive breast cancer tissues in both preand postmenopausal women. In this study, we analyzed expression levels of estrogen-responsive genes (PgR and TFF1), a progesterone-responsive gene (RANKL), ER-related genes (FOXA1 and GATA3), HER2, Ki67 and p53 in ER-positive, HER2-negative breast cancer tissues by IHC.Correlations between expression levels of these molecular markers and clinicopathological factors, including prognosis, were compared between pre-and postmenopausal women. Serum levels of estrone, estradiol, progesterone and testosterone were also measured. Expression levels of PgR, TFF1, RANKL and GATA3 were significantly higher in premenopausal women than in postmenopausal women. Serum estradiol levels were positively correlated with Ki67 labeling index (LI) in premenopausal women, but not in postmenopausal women. High expression of FOXA1 and GATA3 was significantly associated with improved disease-free survival in premenopausal women, but not in postmenopausal women, whereas high expression of PgR and low expression of p53 was significantly correlated with improved disease-free survival in postmenopausal women, but not in premenopausal women. Moreover, the best cutoff points of 3 Ki67 LI for disease-free survival were 30% for premenopausal women and 14% for postmenopausal women. Expression levels of ER, TFF1 and RANKL were not associated with disease-free survival in either pre-or postmenopausal women. Our results suggest that the mechanisms of development and estrogen-dependent growth of ER-positive breast cancer might differ according to menopausal status.

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Promyelocytic leukemia protein (PML) controls breast cancer cell proliferation by modulating Forkhead transcription factors

et al. 2019

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The multitasking promyelocytic leukemia ( PML ) protein was originally recognized as a tumor‐suppressive factor, but more recent evidence has implicated PML in tumor cell prosurvival actions and poor patient prognosis in specific cancer settings. Here, we report that inducible PMLIV expression inhibits cell proliferation as well as self‐renewal and impairs cell cycle progression of breast cancer cell lines in a reversible manner. Transcriptomic profiling identified a large number of PML ‐deregulated genes associated with various cell processes. Among them, cell cycle‐ and division‐related genes and their cognitive regulators are highly ranked. In this study, we focused on previously unknown PML targets, namely the Forkhead transcription factors. PML suppresses the Forkhead box subclass M1 ( FOXM 1) transcription factor at both the RNA and protein levels, along with many of its gene targets. We show that FOXM 1 interacts with PMLIV primarily via its DNA ‐binding domain and dynamically colocalizes in PML nuclear bodies. In parallel, PML modulates the activity of Forkhead box O3 ( FOXO 3), a factor opposing certain FOXM 1 activities, to promote cell survival and stress resistance. Thus, PMLIV affects the balance of FOXO 3 and FOXM 1 transcriptional programs by acting on discrete gene subsets to favor both growth inhibition and survival. Interestingly, PMLIV ‐specific knockdown mimicked ectopic expression vis‐à‐vis loss of proliferative ability and self‐renewal, but also led to loss of survival ability as shown by increased apoptosis. We propose that divergent or similar effects on cell physiology may be elicited by high or low PMLIV levels dictated by other concurrent genetic or epigenetic cancer cell states that may additionally account for its disparate effects in various cancer types.

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Forkhead box proteins: tuning forks for transcriptional harmony

Cited by 599 publications

References 191 publications

FOXO3a and Posttranslational Modifications Mediate Glucocorticoid Sensitivity in B-ALL

FOXO3a and Posttranslational Modifications Mediate Glucocorticoid Sensitivity in B-ALL

Differential expression of progesterone receptor, FOXA1, GATA3, and p53 between pre- and postmenopausal women with estrogen receptor-positive breast cancer

Promyelocytic leukemia protein (PML) controls breast cancer cell proliferation by modulating Forkhead transcription factors

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