In situ hybridization of parathyroid hormone-related protein in normal                skin, skin tumors, and gynecological cancers using digoxigenin-labeled probes and                antibody enhancement.

Danks, Janine A.; McHALE, J. C.; Clark, Simon; Chou, Shao-Ting; Scurry, James; Ingleton, P. M.; Martin, T.J.

doi:10.1177/43.1.7822764

Cited by 27 publications

(21 citation statements)

References 10 publications

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“…These include CCL20 (MIP3), a strong chemoattractant for Langerhans cells (47); CXCL12, which affects T cells; and vascular epidermal growth factor, which plays a role in angiogenesis, cancer, and wound healing (48). In contrast, PTHLH, whose expression is specific for basal cells, is suppressed by SP600125 (49).…”

Section: Table 2 Over-represented Binding Sites For Transcription Facmentioning

confidence: 99%

Inhibition of JNK Promotes Differentiation of Epidermal Keratinocytes

Gazel

Banno

Walsh

et al. 2006

Journal of Biological Chemistry

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In inflamed tissue, normal signal transduction pathways are altered by extracellular signals. For example, the JNK pathway is activated in psoriatic skin, which makes it an attractive target for treatment. To define comprehensively the JNK-regulated genes in human epidermal keratinocytes, we compared the transcriptional profiles of control and JNK inhibitor-treated keratinocytes, using DNA microarrays. We identified the differentially expressed genes 1, 4, 24, and 48 h after the treatment with SP600125. Surprisingly, the inhibition of JNK in keratinocyte cultures in vitro induces virtually all aspects of epidermal differentiation in vivo: transcription of cornification markers, inhibition of motility, withdrawal from the cell cycle, stratification, and even production of cornified envelopes. The inhibition of JNK also induces the production of enzymes of lipid and steroid metabolism, proteins of the diacylglycerol and inositol phosphate pathways, mitochondrial proteins, histones, and DNA repair enzymes, which have not been associated with differentiation previously. Simultaneously, basal cell markers, including integrins, hemidesmosome and extracellular matrix components, are suppressed. Promoter analysis of regulated genes finds that the binding sites for the forkhead family of transcription factors are over-represented in the SP600125-induced genes and c-Fos sites in the suppressed genes. The JNK-induced proliferation appears to be secondary to inhibition of differentiation. The results indicate that the inhibition of JNK in epidermal keratinocytes is sufficient to initiate their differentiation program and suggest that augmenting JNK activity could be used to delay cornification and enhance wound healing, whereas attenuating it could be a differentiation therapy-based approach for treating psoriasis.

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Section: Table 2 Over-represented Binding Sites For Transcription Facmentioning

confidence: 99%

Inhibition of JNK Promotes Differentiation of Epidermal Keratinocytes

Gazel

Banno

Walsh

et al. 2006

Journal of Biological Chemistry

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“…However, this receptor responds to PTH and PTHrP differently from the conventional PTHR1 receptor—normal keratinocytes do not express their gene for the conventional PTHR1 although some might do so during “immortalization” [Henderson et al, 1992; Hanafin et al, 1995; Orloff et al, 1995; Sharpe et al, 1998] And this receptor, whatever it may be, does not couple to adenylyl cyclase, although the keratinocytes have the machinery to do so because they can respond to the β‐adrenergic receptor‐activating isoproterenol with a large burst of adenylyl cyclase activity [Whitfield et al, 1992; Orloff et al, 1995]. Moreover, keratinocytes can be made to respond to PTH‐(1‐34) with a burst of adenylyl cyclase activity if they are engineered to express the conventional PTHR1 receptor [Orloff et al, 1995] However, the TA keratinocytes do not start making the PTHrP to stimulate these unconventional PTH receptors until they have stopped proliferating and lifted off the basal lamina [Juhlin et al, 1992; Danks et al, 1995; reviewed by Whitfield and Chakravarthy, 2001] (Fig. 3).…”

Section: A Different Use For Pths—treating Psoriasismentioning

confidence: 99%

“…And this is could well be the reason for the hyperproliferation because Nicolas et al [2003] have shown that eliminating Notch 1 in mice causes epidermal hyperplasia through a proliferogenic upregulation of β‐catenin and Gli2 expression. And along with these striking differences they don't make PTHrP [Juhlin et al, 1992], probably because of the breakdown of the Notch/Notch ligands mechanism that would normally have restrained β‐catenin and Gli2 expression and driven the stem cell ⇒ TA cell transition, with the resulting stratification, generation of the Ca 2+ gradient and PTHrP expression in the spinous and granular layers [Juhlin et al, 1992; Danks et al, 1995; Lowell et al, 2000; Whitfield and Chakravarthy, 2001; Thélu et al, 2002].…”

Section: A Different Use For Pths—treating Psoriasismentioning

confidence: 99%

Taming psoriatic keratinocytes—PTHs' uses go up another notch

Whitfield

2004

J of Cellular Biochemistry

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The native parathyroid hormone (PTH) and several of its N-terminal adenylyl cyclase-activating fragments and their analogs have become the star stimulators of bone growth for treating osteoporosis, accelerating fracture healing, and strengthening the anchorage of prosthetic bone implants and one of them (Lilly's Forteo--recombinant hPTH-(1-34) has recently arrived in the clinic. But something entirely different has been lurking in the background-the ability of the adenylyl cyclase stimulating hPTH-(1-34) to calm hyperproliferating keratinocytes and reduce psoriatic lesions. By contrast PTH-(7-34) which cannot stimulate adenylyl cyclase actually stimulates keratinocyte proliferation. Normal keratinocytes make PTHrP after they lift off the basal lamina and have stopped cycling. But they have an unconventional PTH/PTHrP receptor which is not coupled to adenylyl cyclase. Psoriatic keratinocytes do not make PTHrP and have only a broken-down, proliferation-limiting terminal differentiation-driving Notch-Notch ligand mechanism. Putting these and other facts together produces a possible picture of an exogenously applied adenylyl cyclase-activating PTH pinch hitting for the missing PTHrP and restoring normal keratinocyte proliferative activity epidermal structure by stimulating dermal fibroblasts which do have the conventional adenylyl cyclase-linked PTHR1 and in response directly or indirectly restore the overlying basal keratinocytes' Notch-Notch ligand terminal differentiation-driving mechanism and consequently a normal epidermal structure.

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“…Parathyroid hormone-related protein has been loca¬ lized by immunohistochemistry in normal skin to basal and spinous keratinocytes (8,9,47,48), and is present consistently in SCCs (8,9,48). However, when these data were adjusted for DNA content, PTHrP secretion decreased with increased DNA content.…”

Section: Discussionmentioning

confidence: 99%

Altered parathyroid hormone-related protein secretion and mRNA expression in squamous carcinoma cells in vitro

Gröne

Weckmann²,

Steinmeyer³

et al. 1996

European Journal of Endocrinology

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Parathyroid hormone-related protein (PTHrP), a major factor in the pathogenesis of humoral hypercalcemia of malignancy, is produced by many squamous carcinoma cells (SCCs). Two SCC lines were grown in multilayered culture systems and compared to cells grown as monolayers to evaluate the effects of cell proliferation, confluence and differentiation on PTHrP secretion and mRNA expression. Well-differentiated (SCC 2/88) and poorly differentiated (SCC-A253) SCCs were grown as monolayer and three-dimensional cultures on collagen-coated membranes to compare the regulation of PTHrP expression and secretion by the cell lines in vitro. Parathyroid hormone-related protein secretion was evaluated by radioimmunoassay and immunohistochemistry. Messenger RNA expression was analyzed by RNase protection assay and in situ hybridization. Secretion of PTHrP was greatest in preconfluent SCC 2/88 cells in monolayer culture and decreased after confluence, which was the result of decreased PTHrP mRNA expression. In contrast, PTHrP secretion in cultures of SCC-A253 cells reached maximal levels after confluence. In multilayered cultures, total PTHrP secretion and mRNA expression remained high in both SCC 2/88 and SCC-A253 cells, and secretion by the multi-layered cultures was principally in the basal direction. Parathyroid hormone-related protein was present in all cell layers in three-dimensional cultures as determined by immunohistochemistry. These results indicated that multilayered cultures of SCCs produced PTHrP continuously, whereas decreased proliferation in monolayer cultures was associated with decreased PTHrP production. Multilayered cultures represent a better system to investigate PTHrP secretion and mRNA expression in vitro and PTHrP secretion by SCCs in vivo may be greatest by proliferating cells.

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In situ hybridization of parathyroid hormone-related protein in normal skin, skin tumors, and gynecological cancers using digoxigenin-labeled probes and antibody enhancement.

Cited by 27 publications

References 10 publications

Inhibition of JNK Promotes Differentiation of Epidermal Keratinocytes

Inhibition of JNK Promotes Differentiation of Epidermal Keratinocytes

Taming psoriatic keratinocytes—PTHs' uses go up another notch

Altered parathyroid hormone-related protein secretion and mRNA expression in squamous carcinoma cells in vitro

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