Insulin-like Growth Factor 1/Insulin Signaling Activates Androgen Signaling through Direct Interactions of Foxo1 with Androgen Receptor

Fan, Wu; Yanase, Toshihiko; Morinaga, Hidetaka; Okabe, Taijiro; Nomura, Masatoshi; Daitoku, Hiroaki; Fukamizu, Akiyoshi; Kato, Shigeaki; Takayanagi, Ryoichi; Nawata, Hajime

doi:10.1074/jbc.m610447200

Cited by 166 publications

(156 citation statements)

References 39 publications

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“…Li et al observed that inhibition of PI3-kinase was able to inhibit the transcriptional activity of AR resulting in decreased androgen-induced proliferation (Li et al, 2001). FOXO1 was found to directly associate with the androgen receptor, and thereby inhibit its transcriptional activity (Li et al, 2003;Fan et al, 2007). Utilizing transcription reporter assays it was shown that AR, in a ligand-dependent manner, could also reciprocally inhibit both FOXO1 and FOXO3 activity.…”

Section: Foxo Partners Regulating Muscle Homeostasismentioning

confidence: 99%

FOXO-binding partners: it takes two to tango

van der Vos,

Coffer

2008

Oncogene

189

161

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Modulation FOXO transcription factor activities can lead to a variety of cellular outputs resulting in changes in proliferation, apoptosis, differentiation and metabolic responses. Although FOXO proteins all contain an identical DNA-binding domain their cellular functions appear to be distinct, as exemplified by differences in the phenotype of Foxo1, Foxo3 and Foxo4 null mutant mice. While some of these differences may be attributable to the differential expression patterns of these transcription factors, many cells and tissues express several FOXO isoforms. Recently it has become clear that FOXO proteins can regulate transcriptional responses independently of direct DNA-binding. It has been demonstrated that FOXOs can associate with a variety of unrelated transcription factors, regulating activation or repression of diverse target genes. The complement of transcription factors expressed in a particular cell type is thus critical in determining the functional end point of FOXO activity. These interactions greatly expand the possibilities for FOXO-mediated regulation of transcriptional programmes. This review details currently described FOXO-binding partners and examines the role of these interactions in regulating cell fate decisions.

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Section: Foxo Partners Regulating Muscle Homeostasismentioning

confidence: 99%

FOXO-binding partners: it takes two to tango

van der Vos,

Coffer

2008

Oncogene

189

161

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“…[175][176][177] IGF-1 stimulates 5α-reductase, adrenal and gonadal androgen synthesis, AR signal transduction, sebocyte proliferation and lipogenesis. [178][179][180][181][182][183][184] Milk consumption results in a significant increase in IGF-1 serum level and exerts strong insulinotropic effects comparable to high glycaemic food. 185,186 Insulin induces hepatic IGF-1 secretion, and both hormones amplify the stimulatory effect of GH on sebocytes and augment mitogenic downstream signaling pathways of insulin receptors, IGF-1 receptor and FGFR2b (Fig.…”

Section: Interleukin-1α Network In Keratinocytesmentioning

confidence: 99%

Role of FGFR2-signaling in the pathogenesis of acne

Melnik

2009

Dermato-Endocrinology

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It is the purpose of this review to extend our understanding of the fibroblast growth factor (FGF) receptor-2b-signaling network in the pathogenesis of acne. A new concept of the role of FGFR2b-signaling in dermal-epithelial interaction for skin appendage formation, pilosebaceous follicle homeostasis, comedogenesis, sebaceous gland proliferation and lipogenesis is presented. The FGFR2-gain-of-function mutations in Apert syndrome and unilateral acneiform nevus are most helpful model diseases pointing the way to androgen-dependent dermalepithelial FGFR2-signaling in acne. Androgen-mediated upregulation of FGFR2b-signaling in acne-prone skin appears to be involved in the pathogenesis of acne vulgaris. In organotypic skin cultures, keratinocyte-derived interleukin-1α stimulated fibroblasts to secrete FGF7 which stimulated FGFR2b-mediated keratinocyte proliferation. Postnatal deletion of FGFR2b in mice resulted in severe sebaceous gland atrophy. The importance of FGFR2b in sebaceous gland physiology is further supported by the mode of action of anti-acne agents which have been proposed to attenuate FGFR2b-signaling. Downregulation of FGFR2b-signaling by isotretinoin explains its therapeutic effect in acne. Downregulation of FGFR2b-signaling during the first trimester of pregnancy disturbs branched morphogenesis and explains retinoid embryotoxicity. Insulin-like growth factor-1 (IGF-1), the mediator of growth hormone during puberty, intracts with androgen-dependent FGFR2b-signaling and links androgen-and FGF-mediated signal transduction important in sebaceous gland homeostasis. The search for a follicular defect in the dermalepithelial regulation of growth factor-signaling in acne-prone skin appears to be a most promising approach to clarify the pathogenesis of acne.

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“…(55) A recent study showed that PI3K/Akt pathway inhibited the activity of Foxo1, which is a corepressor for AR, providing another mechanism of AR activation through this pathway. (56) In the context of the PI3K/Akt pathway, it is important to mention the phosphatase and tensin homolog deleted on chromosome ten (PTEN), also known as mutated in multiple advanced cancers (MMAC1), which is a negative regulator of the PI3K/Akt pathway. (57) FISH analyses have indicated that about 70% of primary prostate cancer samples and about 20% of the high grade PIN (prostatic intraepithelial neoplasia) samples have genomic deletions of PTEN.…”

Section: Tmprss2mentioning

confidence: 99%

Androgen signaling and its interactions with other signaling pathways in prostate cancer

2007

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SummaryProstate cancer is the most frequently diagnosed nonskin cancer and the third leading cause of cancer mortality in men. In the initial stages, prostate cancer is dependent on androgens for growth, which is the basis for androgen ablation therapy. However, in most cases, prostate cancer progresses to a hormone refractory phenotype for which there is no effective therapy available at present. The androgen receptor (AR) is required for prostate cancer growth in all stages, including the relapsed, ''androgen-independent'' tumors in the presence of very low levels of androgens. This review focuses on AR function and AR-target genes and summarizes the major signaling pathways implicated in prostate cancer progression, their crosstalk with each other and with AR signaling. This complex network of interactions is providing a deeper insight into prostate carcinogenesis and may form the basis for novel diagnostic and therapeutic strategies. IntroductionProstate adenocarcinoma is the most frequently diagnosed non-cutaneous male malignancy and the third leading cause of cancer-related death in men in most western industrialized countries. (1) It is estimated that around 660,000 men worldwide will be diagnosed with prostate cancer and 250,000 men will die from it in 2010; thus, it will remain a major health problem in the future. (1) It was more than 60 years ago that the important role of male sex hormones (androgens) for the development and growth of prostate cancer was demonstrated. (2) Accordingly, androgen ablation therapy has been the main line of therapy for prostate cancer. Therefore, much of the focus in prostate cancer research to date has naturally been on androgens, how to decrease the androgens in the circulation and how to inhibit the androgen receptor (AR).In addition to AR signaling, it has now become evident that other signaling pathways, as well as non-genomic and genomic alterations, are involved in prostate cancer development and progression. Furthermore, recent studies indicated that signaling through AR has a critical role even after androgen ablation and disease progression (for review see Ref.3). In the following sections, we give an overview of androgen signaling in prostate cancer, with a special focus on recent findings about AR function and AR target genes. We then review the involvement of other central signaling pathways in prostate cancer, with a special focus on their cross-talk with the AR signaling pathway. Clinical implications of these findings and potential directions for future research are also outlined.

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Insulin-like Growth Factor 1/Insulin Signaling Activates Androgen Signaling through Direct Interactions of Foxo1 with Androgen Receptor

Cited by 166 publications

References 39 publications

FOXO-binding partners: it takes two to tango

FOXO-binding partners: it takes two to tango

Role of FGFR2-signaling in the pathogenesis of acne

Androgen signaling and its interactions with other signaling pathways in prostate cancer

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