Evidence That Fibulin Family Members Contribute to the Steroid-dependent Extravascular Sequestration of Sex Hormone-binding Globulin

Ng, Kwong-Man; Catalano, Maria Graziella; Pinós, Tomàs; Selva, David M.; Avvakumov, G.V.; Munell, Francina; Hammond, Geoffrey L.

doi:10.1074/jbc.m512370200

Cited by 56 publications

(46 citation statements)

References 51 publications

(56 reference statements)

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“…Human ovary tissue has been shown to express high levels of fibulin-2 mRNA (30). Moreover, a recent study suggests that fibulin-2 and fibulin-1 may be involved in sequestering sex hormone-binding globulin within the uterine stroma and epididymis, thereby controlling sex-steroid access to target cells (15). However, the results presented here show that both male and female Fbln2 Ϫ/Ϫ mice are fertile, indicating that fibulin-2 is not required for normal reproductive function.…”

Section: Discussionmentioning

confidence: 99%

Fibulin-2 Is Dispensable for Mouse Development and Elastic Fiber Formation

Sicot¹,

Tsuda²,

Markova³

et al. 2008

Molecular and Cellular Biology

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Fibulin-2 is an extracellular matrix protein belonging to the five-member fibulin family, of which two members have been shown to play essential roles in elastic fiber formation during development. Fibulin-2 interacts with two major constituents of elastic fibers, tropoelastin and fibrillin-1, in vitro and localizes to elastic fibers in many tissues in vivo. The protein is prominently expressed during morphogenesis of the heart and aortic arch vessels and at early stages of cartilage development. To examine its role in vivo, we generated mice that do not express the fibulin-2 gene (Fbln2) through homologous recombination of embryonic stem cells. Unexpectedly, the fibulin-2-null mice were viable and fertile and did not display gross and anatomical abnormalities. Histological and ultrastructural analyses revealed that elastic fibers assembled normally in the absence of fibulin-2. No compensatory up-regulation of mRNAs for other fibulin members was detected in the aorta and skin tissue. However, in the fibulin-2 null aortae, fibulin-1 immunostaining was increased in the inner elastic lamina, where fibulin-2 preferentially localizes. The results demonstrate that fibulin-2 is not required for mouse development and elastic fiber formation and suggest possible functional redundancy between fibulin-1 and fibulin-2.

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Section: Discussionmentioning

confidence: 99%

Fibulin-2 Is Dispensable for Mouse Development and Elastic Fiber Formation

Sicot¹,

Tsuda²,

Markova³

et al. 2008

Molecular and Cellular Biology

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“…Although the extra carbohydrate chain encoded by the 356N variant is unlikely to alter the affinity of SHBG for testosterone or other hormones (26,27), it may affect the binding of SHBG to other proteins or receptors, as glycosylation is thought to be important in cell membrane signal transduction for other glycoprotein hormones (28) and for the attachment of SHBG to cell membranes (29). The extent of glycosylation is reported to affect the ability of SHBG to interact with matrix-associated proteins (30). Thus, it is possible that the SHBG 356N variant may increase prostate cancer risk by altering protein or receptor binding.…”

Section: Discussionmentioning

confidence: 99%

Variant in Sex Hormone-Binding Globulin Gene and the Risk of Prostate Cancer

Berndt

Chatterjee

Huang

et al. 2007

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Sex hormones have been implicated in prostate carcinogenesis and are thought to modulate cell proliferation and growth. To investigate the association between polymorphisms in hormone-related genes and prostate cancer risk, we conducted a two-stage, case-control study within the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Using DNA extracted from blood specimens, we initially genotyped 14 single nucleotide polymorphisms in genes involved in hormone regulation or metabolism (AKR1C3, CYP1A1, CYP1B1, CYP3A4, ESR1, GNRH1, HSD173B, HSD3B2, SHBG, and SRD5A2) in 488 prostate cancer cases and 617 matched controls. Heterozygotes at SHBG D356N were found to be associated with an increased risk of prostate cancer compared with the homozygous wild type, particularly among non-Hispanic whites (odds ratio, 1.54; 95% confidence interval, 1.13-2.09; P = 0.006). No significant associations were observed with the other polymorphisms. The SHBG D356N polymorphism, which has potential functional significance, was subsequently genotyped in additional 769 cases and 1,168 controls. Overall, SHBG D356N heterozygotes were found to have an increased risk of prostate cancer among whites (odds ratio, 1.34; 95% confidence interval, 1.10-1.63; P = 0.0007). This study suggests that genetic variation in SHBG may influence prostate cancer susceptibility. (Cancer Epidemiol Biomarkers Prev 2007;16(1):165 -8)

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“…140 In mice, the epididymis has the highest expression of fibulin-1D and fibulin-2, possibly attributable to their interaction with interstitial sex hormone-binding globulin. 141 The transcript of fibulin-5, which antagonizes VEGF signalling and inhibits endothelial sprouting, is expressed in the entire epididymis of rats and mice, especially in the corpus region (http://www.mrg.genetics.washington. edu/).…”

Section: Rarity Of Epididymal Cancermentioning

confidence: 99%

Why are epididymal tumours so rare?

Yeung¹,

Wang²,

Cooper³

2012

Asian J Androl

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Epididymal tumour incidence is at most 0.03% of all male cancers. It is an enigma why the human epididymis does not often succumb to cancer, when it expresses markers of stem and cancer cells, and constitutively expresses oncogenes, pro-proliferative and pro-angiogenic factors that allow tumour cells to escape immunosurveillance in cancer-prone tissues. The privileged position of the human epididymis in evading tumourigenicity is reflected in transgenic mouse models in which induction of tumours in other organs is not accompanied by epididymal neoplasia. The epididymis appears to: (i) prevent tumour initiation (it probably lacks stem cells and has strong anti-oxidative mechanisms, active tumour suppressors and inactive oncogene products); (ii) foster tumour monitoring and destruction (by strong immuno-surveillance and -eradication, and cellular senescence); (iii) avert proliferation and angiogenesis (with persistent tight junctions, the presence of anti-angiogenic factors and misplaced pro-angiogenic factors), which together (iv) promote dormancy and restrict dividing cells to hyperplasia. Epididymal cells may be rendered non-responsive to oncogenic stimuli by the constitutive expression of factors generally inducible in tumours, and resistant to the normal epididymal environment, which mimics that of a tumour niche promoting tumour growth. The threshold for tumour initiation may thus be higher in the epididymis than in other organs. Several anti-tumour mechanisms are those that maintain spermatozoa quiescent and immunologically silent, so the low incidence of cancer in the epididymis may be a consequence of its role in sperm maturation and storage. Understanding these mechanisms may throw light on cancer prevention and therapy in general.

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Evidence That Fibulin Family Members Contribute to the Steroid-dependent Extravascular Sequestration of Sex Hormone-binding Globulin

Cited by 56 publications

References 51 publications

Fibulin-2 Is Dispensable for Mouse Development and Elastic Fiber Formation

Fibulin-2 Is Dispensable for Mouse Development and Elastic Fiber Formation

Variant in Sex Hormone-Binding Globulin Gene and the Risk of Prostate Cancer

Why are epididymal tumours so rare?

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