Corticotropin Releasing Hormone and Related Peptides Can Act as Bioregulatory Factors in Human Keratinocytes

Słomiński, Andrzej; Roloff, B.; Zbytek, Blazej; Wei, E.T.; Fechner, Klaus; Curry, Jonathan L.; Wortsman, Jacobo

doi:10.1290/1071-2690(2000)036<0211:crharp>2.0.co;2

Cited by 56 publications

(37 citation statements)

References 30 publications

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“…Additional studies to define the expression of this receptor and its ligands in various human malignancies are required, as is work to clarify what appears to be a positive feedback loop whereby Ucn2 induces its own receptor. Although only observational in this study, we did delineate two interesting Ucn2-related phenomena that we and others have previously observed in response to CRF-pathway modulation; altered cellular morphology and evidence of altered vascular permeability (20)(21)(22)(23)(24). Specifically, we observed enlargement and flattening/spreading of LLCCs when exposed to Ucn2.…”

Section: Discussionsupporting

confidence: 51%

Urocortin2 inhibits tumor growth via effects on vascularization and cell proliferation

Hao

Huang

Cleman

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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The corticotropin-releasing factor (CRF) receptor CRFR2 is expressed widely in peripheral tissues and in the vasculature, although its functional roles in those tissues have only recently begun to be elucidated. Previously we found that genetic deletion of CRFR2 resulted in profound postnatal hypervascularization in mice, characterized by both an increase in total vessel number and a dramatic increase in vessel diameter. These data strongly suggested that ligands for CRFR2 act to limit tissue vascularity, perhaps as a counterbalance to factors that promote neovascularization. Urocortin 2 (Ucn2) is a specific ligand for the CRFR2. We hypothesized that activation of CRFR2 by Ucn2 might thus suppress tumor vascularization and consequently limit tumor growth. Here, we show that viral-mediated expression of Ucn2 strikingly inhibits the growth and vascularization of Lewis Lung Carcinoma Cell (LLCC) tumors in vivo. Further, we found that this effect on tumor growth inhibition was independent of whether exposure to Ucn2 occurred before or after establishment of measurable tumors. In vitro, Ucn2 directly inhibited the proliferation of LLCC, suggesting that the tumor-suppressing effects of CRFR2 activation involve a dual mechanism of both a direct inhibition of tumor cell cycling and the suppression of tumor vascularization. These results establish that Ucn2 inhibits tumor growth, suggesting a potential therapeutic role for CRFR2 ligands in clinical malignancies.anti-angiogenic ͉ cancer ͉ CRF ͉ peptide ͉ CRFR2

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Section: Discussionsupporting

confidence: 51%

Urocortin2 inhibits tumor growth via effects on vascularization and cell proliferation

Hao

Huang

Cleman

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…In the human skin, CRH-R1 is predominantly expressed in the epidermis with CRH-R1α being the major isoform present (Slominski et al, 2004a). The cutaneous CRH-R1 is activated by CRH or urocortin and its intracellular signal transduction pathways are coupled to cAMP, IP3 or Ca (Fazal et al, 1998;Slominski et al, 2006b;Slominski et al, 1999c;Slominski et al, 2000e;Wiesner et al, 2003;Zbytek and Slominski, 2005). UV radiation and factors raising intracellular cAMP increase CRH-R1α expression and change the pattern of isoform expression Slominski et al, 2001).…”

Section: Cutaneous Crh Signaling Systemmentioning

confidence: 99%

Differential expression of HPA axis homolog in the skin

Slominski

Wortsman

Tuckey

et al. 2007

Molecular and Cellular Endocrinology

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249

267

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SummaryHuman skin expresses elements of the hypothalamo-pituitary-adrenal (HPA) axis including proopiomelanocortin (POMC), corticotropin releasing hormone (CRH), the CRH receptor-1 (CRH-R1), key enzymes of corticosteroid synthesis and synthesizes glucocorticoids. Expression of these elements is organized in functional, cell type-specific regulatory loops, which imitate the signaling structural hierarchy of the HPA axis. In melanocytes and fibroblasts CRH-induced CRH-R1 stimulation upregulates POMC expression and production of ACTH through activation of cAMP dependent pathway(s). Melanocytes respond with enhanced production of cortisol and corticosterone, which is dependent on POMC activity. Fibroblasts respond to CRH and ACTH with enhanced production of corticosterone, but not cortisol, which is produced constitutively. Organcultured human scalp hair follicles also show a fully functional HPA axis equivalent, including cortisol synthesis and secretion and negative feedback regulation by cortisol on CRH expression. Thus differential, CRH-driven responses of skin reproduce key features of the central HPA axis at the tissue/single cell levels.

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“…Human keratinocytes express several isoforms of CRH receptor type 1 (CRH-R1) . CRH inhibits proliferation of both human primary and immortalized keratinocytes (Quevedo et al 2001, Slominski et al 2000a. CRH increases cyclic adenosine monophosphate (cAMP) production levels in immortalized keratinocytes (Slominski et al 2000a) and calcium levels in both immortalized and human primary keratinocytes (Fazal et al 1998, Slominski et al 1999, Wiesner et al 2002.…”

Section: Introductionmentioning

confidence: 99%

Corticotropin-releasing hormone stimulates NF-kappaB in human epidermal keratinocytes

Zbytek¹,

Pfeffer²,

Słomiński³

2004

Journal of Endocrinology

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Corticotropin-releasing hormone (CRH) has been shown to inhibit proliferation and modulate expression of inflammation markers in the epidermal cells. In the present study we report that CRH also stimulates nuclear factor-kappa B (NF-B) activity. Incubation with CRH of human keratinocytes derived from primary cultures resulted in increased binding of DNA by NF-B. CRH induced translocation of NF-B subunit p65 from the cytoplasm to the nucleus and induced expression of B-driven chloramphenicol acetyltransferase (CAT)reporter gene. NF-B translocation was accompanied by degradation of the inhibitor of NF-B (I B-). Specificity of the CRH effect was demonstrated by the use of CRH-R antagonists antalarmin and -helical CRH . CRH-dependent stimulation of NF-B activity is consistent with accumulated data about role of this neuropeptide in the regulation of local epidermal homeostasis.

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Corticotropin Releasing Hormone and Related Peptides Can Act as Bioregulatory Factors in Human Keratinocytes

Cited by 56 publications

References 30 publications

Urocortin2 inhibits tumor growth via effects on vascularization and cell proliferation

Urocortin2 inhibits tumor growth via effects on vascularization and cell proliferation

Differential expression of HPA axis homolog in the skin

Corticotropin-releasing hormone stimulates NF-kappaB in human epidermal keratinocytes

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