Age-Related Expression of PEDF/EPC-1 in Human Endometrial Stromal Fibroblasts: Implications for Interactive Senescence

Palmieri, Diane; Watson, Janet; Rinehart, Clifford A.

doi:10.1006/excr.1998.4341

Cited by 50 publications

(39 citation statements)

References 28 publications

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“…Matrigel plugs were treated with rPEDF, plPEDF, or the various mutants in combination with bFGF (300 ng/mL). As expected, 21,26 control plugs treated with PBS showed a very minute angiogenic response, bFGFtreated plugs showed robust angiogenic activity, and the rPEDF, plPEGF, as well as the S24,114E and S24,114A mutants exhibited the previously decribed 31 antiangiogenic activity in the system ( Figure 5). The triple mutants EEE or EEA reduced bFGF-induced angiogenesis to a degree that was roughly similar to the effect of S24,114E, while AAA and AAE mutants had only a minor effect that was roughly similar to that of S24,114A.…”

Section: The Effect Of the Triple Mutation On The Pedf-induced Antiansupporting

confidence: 77%

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Variable phosphorylation states of pigment-epithelium–derived factor differentially regulate its function

Maik-Rachline

Seger

2006

Blood

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The pigment epithelium-derived factor (PEDF) belongs to the family of noninhibitory serpins. Although originally identified in the eye, PEDF is widely expressed in other body regions including the plasma. This factor can act either as a neurotrophic or as an antiangiogenic factor, and we previously showed that the 2 effects of PEDF are regulated through phosphorylation by PKA and CK2. Here, we studied the interplay between the PKA and CK2 phosphorylation of PEDF, and found that a PEDF mutant mimicking the CK2-phosphorylated PEDF cannot be phosphorylated by PKA, while the mutant mimicking the PKA-phosphorylated PEDF is a good CK2 substrate. Using triple mutants that mimic the PKA-and CK2-phosphorylated and nonphosphorylated PEDF, we found that PEDF can induce several distinct cellular activities dependent on its phosphorylation. The mutant mimicking the accumulative PKA plus CK2 phosphorylation exhibited the strongest antiangiogenic and neurotrophic activities, while the mutants mimicking the individual phosphorylation site mutants had either a reduced activity or only one of these activities. Thus, differential phosphorylation induces variable effects of PEDF, and therefore contributes to the complexity of PEDF action. It is likely that the triple phosphomimetic mutant can be used to generate effective antiangiogenic or neurotrophic drugs. IntroductionThe pigment epithelium-derived factor (PEDF) is a member of the serine protease inhibitors (serpin) superfamily, but as of today was not found to exhibit inhibitory activity against any proteases. 1,2 It was first isolated based on its ability to convert dividing retinoblastoma cells into differentiated neurons, and thus was characterized as a neurotrophic factor. 1,3 Later, it was shown that besides its neurotrophic functions, PEDF is a potent natural inhibitor of angiogenesis in the eye, 4 where it inhibits stimulatory activity of several strong proangiogenic factors. This antiangiogenic potency has also been shown in several animal models in which PEDF was demonstrated as the factor responsible for the reduction of bloodvessel growth in the eye. [5][6][7][8][9] Although originally discovered in the culture medium of pigment epithelial cells obtained from the fetal human retina, 10 it is clear today that PEDF is expressed not only in the retina, but also at multiple sites in the adult eye, [11][12][13] as well as in the adult human brain, the spinal cord, 14,15 and human plasma. 16 Therefore, it is possible that PEDF has the potential to inhibit angiogenesis throughout the body.It is well established that protein phosphorylation plays a key role in the regulation of most intracellular processes. However, it is becoming increasingly evident that protein kinases can also regulate extracellular processes, as the kinases are present extracellularly as either ectoprotein or exoprotein kinases. 17,18 The ectoprotein kinases are membrane-bound enzymes whose catalytic activities are localized on the extracellular cell surface of a wide variety of cells. The exoprotein k...

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Section: The Effect Of the Triple Mutation On The Pedf-induced Antiansupporting

confidence: 77%

“…PEDF was previously shown to inhibit cell proliferation of endometrial carcinoma cells 31 and to induce apoptosis of endothelial cells. 5 We were therefore interested in determining the effect of PEDF and its phosphorylation on HUVEC proliferation.…”

Section: The Effect Of Pedf Mutants On Cell Proliferationmentioning

confidence: 99%

Variable phosphorylation states of pigment-epithelium–derived factor differentially regulate its function

Maik-Rachline

Seger

2006

Blood

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“…Increasing amount of evidence indicates that under physiologic conditions, an essential balance between PEDF and VEGF exists, and PEDF may counteract the angiogenic potential of VEGF (17). Several studies showed that PEDF level declines with age, and suggested that this decline may play a key role in the development of angiogenic-related pathologies (18). Moreover, it was shown that decrease in PEDF expression is one of the mechanisms that promote tumor growth (19), suggesting PEDF as an anticancer therapy (20,21).…”

Section: Introductionmentioning

confidence: 99%

Pigment Epithelium–Derived Factor Alleviates Tamoxifen-Induced Endometrial Hyperplasia

Goldberg

Bar‐Joseph

Grossman

et al. 2015

Molecular Cancer Therapeutics

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Tamoxifen is a cornerstone component of adjuvant endocrine therapy for patients with hormone-receptor-positive breast cancer. Its significant adverse effects include uterine hyperplasia, polyps, and increased risk of endometrial cancer. However, the underlying molecular mechanism remains unclear. Excessive angiogenesis, a hallmark of tumorigenesis, is a result of disrupted balance between pro-and anti-angiogenic factors. VEGF is a proangiogenic factor shown to be elevated by tamoxifen in the uterus. Pigment epithelium-derived factor (PEDF) is a potent anti-angiogenic factor that suppresses strong pro-angiogenic factors, such as VEGF. Our aim was to investigate whether angiogenic balance plays a role in tamoxifen-induced uterine pathologies, elucidate the molecular impairment in that network, and explore potential intervention to offset the proposed imbalance elicited by tamoxifen. Using in vivo mouse models, we demonstrated that tamoxifen induced a dose-dependent shift in endogenous uterine angiogenic balance favoring VEGF over PEDF. Treatment with recombinant PEDF (rPEDF) abrogated tamoxifen-induced uterine hyperplasia and VEGF elevation, resulting in reduction of blood vessels density. Exploring the molecular mechanism revealed that tamoxifen promoted survival and malignant transformation pathways, whereas rPEDF treatment prevents these changes. Activation of survival pathways was decreased, demonstrated by reduction in AKT phosphorylation concomitant with elevation in JNK phosphorylation. Estrogen receptor-a and c-Myc oncoprotein levels were reduced. Our findings provide novel insight into the molecular mechanisms tamoxifen induces in the uterus, which may become the precursor events of subsequent endometrial hyperplasia and cancer. We demonstrate that rPEDF may serve as a useful intervention to alleviate the risk of tamoxifen-induced endometrial pathologies.

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“…Yet, the specific mechanisms leading to angiogenesis, migration, and/or proliferation of endometrial endothelial cells still need to be elucidated (Girling & Rogers 2009). The first report for PEDF function in the endometrium was given by Palmieri et al (1999); they followed agerelated changes in the level of PEDF and their effect on tumorigenicity. This group reported that PEDF level decreased with age and suggested that this decrease can contribute to the age-related increase in cancer incidence.…”

Section: The Role Of Pedf In Endometrial Physiology and Pathologymentioning

confidence: 99%

Role of pigment epithelium-derived factor in the reproductive system

Chuderland¹,

Ben‐Ami²,

Bar‐Joseph³

et al. 2014

Reproduction

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The physiological function of the female reproductive organs is hormonally controlled. In each cycle, the reproductive organs undergo tissue modifications that are accompanied by formation and destruction of blood vessels. Proper angiogenesis requires an accurate balance between stimulatory and inhibitory signals, provided by pro-and anti-angiogenic factors. As with many other tissues, vascular endothelial growth factor (VEGF) appears to be one of the major pro-angiogenic factors in the female reproductive organs. Pigment epithelium-derived factor (PEDF) is a non-inhibitory member of the serine protease inhibitors (serpin) superfamily, possessing potent physiologic anti-angiogenic activity that negates VEGF activity. The role of PEDF in decreasing abnormal neovascularization by exerting its anti-angiogenic effect that inhibits pro-angiogenic factors, including VEGF, has been investigated mainly in the eye and in cancer. This review summarizes the function of PEDF in the reproductive system, showing its hormonal regulation and its anti-angiogenic activity. Furthermore, some pathologies of the female reproductive organs, including endometriosis, ovarian hyperstimulation syndrome, polycystic ovary syndrome, and others, are associated with a faulty angiogenic process. This review illuminates the role of PEDF in their pathogenesis and treatment. Collectively, we can conclude that although PEDF seems to play an essential role in the physiology and pathophysiology of the reproductive system, its full role and mechanism of action still need to be elucidated.Reproduction (2014) 148 R53-R61

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Age-Related Expression of PEDF/EPC-1 in Human Endometrial Stromal Fibroblasts: Implications for Interactive Senescence

Cited by 50 publications

References 28 publications

Variable phosphorylation states of pigment-epithelium–derived factor differentially regulate its function

Variable phosphorylation states of pigment-epithelium–derived factor differentially regulate its function

Pigment Epithelium–Derived Factor Alleviates Tamoxifen-Induced Endometrial Hyperplasia

Role of pigment epithelium-derived factor in the reproductive system

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