Expression of TGF-beta related Smad proteins in human epithelial skin tumors.

Lange, D.; Persson, Urban; Wollina, Uwe; Dijke, Peter ten; Castelli, E.; Ch, Heldin; Funa, Keiko

doi:10.3892/ijo.14.6.1049

Cited by 26 publications

(33 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The involvement of TGF-β1 signaling in the control of the homeostasis of the epidermis has been confirmed in vivo in various transgenic mouse models (Cui et al, 1995;Wang et al, 1997;Amendt et al, 1998), and suggested in humans by clinical observations showing that a dysregulation of the TGF-β1 signaling cascade is often associated with the malignant conversion of skin keratinocytes (Lange et al, 1999). However, although these in vivo observations confirmed the inhibition of keratinocyte cell cycling described in vitro with high concentrations of TGF-β1, they do not provide any information about the positive effect of TGF-β1 on immature keratinocyte expansion, as demonstrated in this in vitro study with very low concentrations (10-30 pg/ml).…”

Section: Discussionmentioning

confidence: 94%

Long-term expansion of human functional epidermal precursor cells: promotion of extensive amplification by low TGF-β1 concentrations

Fortunel

Hatzfeld

Rosemary

et al. 2003

Journal of Cell Science

View full text Add to dashboard Cite

IntroductionTwo major obstacles to the study of adult somatic stem cells are the paucity of specific selection markers and our current inability to understand fully the controls of stemness and to exploit the capacity for stem cell self-renewal. In two previous issues of J. Cell Sci. (Fortunel et al., 1998;Batard et al., 2000), we have introduced the working model of high proliferative potential-quiescent (HPP-Q) cells to refer to primitive human hematopoietic progenitor cells, on which transforming growth factor-β1 (TGF-β1) exerts an important regulatory role. According to this model, (1) TGF-β1 maintains these cells in a quiescent or slow-cycling state, in part by downmodulating various cytokine receptors, resulting in a mitogenic receptor low phenotype, and thus providing a tool to select this subpopulation (Fortunel et al., 1998); and (2) TGF-β1 may also participate in the control of hematopoietic stem/progenitor cell immaturity. This second function is suggested by the fact that TGF-β1 maintains a high level of the cell-surface expression of hematopoietic cell immaturity markers, such as CD34, throughout successive divisions (Batard et al., 2000). However, because hematopoietic stem and progenitor cells spontaneously differentiate into several lineages and do not remain as a homogenous population in culture, it appeared complex to study the effect of TGF-β1 on long-term selfrenewal in this system. As presented in this report, we found that the human epidermal precursor cell compartment represents a unique model to analyze the effect of TGF-β1 on long-term self-renewal of functional undifferentiated somatic cells.Most studies performed to identify cell-surface markers expressed by primitive keratinocytes have focused on molecules involved in cell adhesion. It has been reported that early keratinocytes of the basal layer of the epidermis express the α2β1 and α3β1 integrins (Peltonen et al., 1989; Carter et 4043We have previously introduced the concept of high proliferative potential-quiescent (HPP-Q) cells to refer to primitive human hematopoietic progenitors, on which transforming growth factor-β1 (TGF-β1) exerts a pleiotropic effect. TGF-β1 confers to these slow-dividing cells a mitogenic receptor low phenotype and maintains immature properties by preventing differentiation and apoptosis. However, the effect of TGF-β1 on long-term expansion has not yet been clearly demonstrated. Here, we describe the characterization of a human skin keratinocyte subpopulation, highly enriched for primitive epidermal precursors, on the basis of high adhesion capacity (Adh +++ ) and low expression of the epidermal growth factor receptor (Adh +++ EGF-R low ). In our standard culture condition without feeder cells, the mean estimated output for cells from an unfractionated population of primary foreskin keratinocytes was 10 7 -10 8 , increasing to 10 12 -10 13 in cultures initiated with selected Adh +++ EGF-R low precursors. Characterization of these cells revealed a hitherto unknown property of TGF-β1: its addition at a very l...

show abstract

Section: Discussionmentioning

confidence: 94%

Long-term expansion of human functional epidermal precursor cells: promotion of extensive amplification by low TGF-β1 concentrations

Fortunel

Hatzfeld

Rosemary

et al. 2003

Journal of Cell Science

View full text Add to dashboard Cite

show abstract

“…In addition, many studies have shown that TGF-h acts as a tumor suppressor during the early stages of skin carcinogenesis (6,7,39,40). Furthermore, expression of Smads is found to be downregulated in chemically induced mouse epidermal tumors and human basal cell carcinomas (25). Although the molecular mechanisms of TGF-h signaling in the inhibition of epidermal cell proliferation and tumor formation have been uncovered to great molecular details, corroborating in vivo evidence is still lacking (13).…”

Section: Discussionmentioning

confidence: 99%

“…The eight identified Smad proteins have been divided into three functional classes: the receptorregulated Smads (Smad1, 2, 3, 5, and 8), the comediator Smad (Smad4), and the inhibitory Smads (Smad6 and Smad7). Previous studies have shown that the expression of Smads is markedly decreased in basal cell carcinomas (25), chemically induced squamous cell carcinomas (26), and some head and neck squamous cell carcinomas (27), which suggests that Smads play a role in skin carcinogenesis. Additional evidence has implicated Smad3 in the inhibition of reepithelialization, specifically via effects on keratinocyte proliferation (28).…”

Section: Introductionmentioning

confidence: 99%

Targeted Disruption of Smad4 in Mouse Epidermis Results in Failure of Hair Follicle Cycling and Formation of Skin Tumors

et al. 2005

View full text Add to dashboard Cite

Smad4 is the common mediator of transforming growth factor-B (TGF-B) superfamily signaling, which functions in diverse developmental processes in mammals. To study the role of Smad4 in skin development, a keratinocyte-specific null mutant of Smad4 (Smad4 co/co ;K5-Cre) was generated in mice using the Cre-loxP system. The Smad4-mutant mice exhibited progressive alopecia as a result of the mutant hair follicles failing to undergo programmed regression. Sonic hedgehog (Shh) was only detected in Smad4-mutant hair follicles at the catagen stage. Seventy percent of Smad4 co/co ; K5-Cre mice developed spontaneous tumors within 12 months of birth. c-Myc and cyclin D1 were up-regulated whereas p21 and p27 expressions were decreased, which correlated with the epidermal hyperplasia in Smad4 mutants. Interestingly, coordinated deletion of the Smad4 and PTEN genes resulted in accelerated hair loss and skin tumor formation, suggesting that Smad4 and PTEN act synergistically to regulate epidermal proliferation and differentiation. All of our data indicate that Smad4 is essential for catagen induction and acts as a critical suppressor in skin tumorigenesis. (Cancer Res 2005; 65(19): 8671-8)

show abstract

Section: Discussionmentioning

confidence: 99%

“…VIP-binding sites have been described in astrocytes (32) as well as in endothelial cells (33). In both cases, developmental functions (33,34) fects involving normal growth and cancer proliferation. The abundance of ADNP mRNA in heart, skeletal muscle, kidney, and placenta may represent, in part, an astrocyte-like cell population (38) or enrichment in blood microvessels (39).…”

Section: Discussionmentioning

confidence: 99%

Cloning and Characterization of the Human Activity-dependent Neuroprotective Protein

Zamostiano¹,

Pinhasov²,

Gelber³

et al. 2001

Journal of Biological Chemistry

226

250

View full text Add to dashboard Cite

We have recently cloned the mouse activity-dependent neuroprotective protein (ADNP). Here, we disclose the cloning of human ADNP (hADNP) from a fetal brain cDNA library. Comparative sequence analysis of these two ADNP orthologs indicated 90% identity at the mRNA level. Several single nucleotide polymorphic sites were noticed. The deduced protein structure contained nine zinc fingers, a proline-rich region, a nuclear bipartite localization signal, and a homeobox domain profile, suggesting a transcription factor function. Further comparative analysis identified an ADNP paralog (33% identity and 46% similarity), indicating that these genes belong to a novel protein family with a nine-zinc finger motif followed by a homeobox domain. The hADNP gene structure spans ϳ40 kilobases and includes five exons and four introns with alternative splicing of an untranslated second exon. The hADNP gene was mapped to chromosome 20q12-13.2, a region associated with aggressive tumor growth, frequently amplified in many neoplasias, including breast, bladder, ovarian, pancreatic, and colon cancers. hADNP mRNA is abundantly expressed in distinct normal tissues, and high expression levels were encountered in malignant cells. Down-regulation of ADNP by antisense oligodeoxynucleotides up-regulated the tumor suppressor p53 and reduced the viability of intestinal cancer cells by 90%. Thus, ADNP is implicated in maintaining cell survival, perhaps through modulation of p53.Mouse activity-dependent neuroprotective protein (mADNP), 1 a novel vasoactive intestinal peptide (VIP)-responsive gene, was recently cloned (1). The relative enrichment of mADNP transcripts in the cerebellum, cortex, hippocampus, medulla, and midbrain and the increases found in the presence of VIP, an established neuroprotective substance (2), implied a potential function in brain metabolism. Specifically, mADNP mRNA increased 2-3-fold in astroglial cells incubated for 3 h in the presence of nanomolar amounts of VIP (1). Another tissue containing increased mADNP transcripts is the mouse testis, a highly proliferative tissue, suggesting the involvement of ADNP in cell division.As deregulation of oncogenes has been associated with neurodegeneration (3), pathways that regulate neuronal survival may impinge upon cancer proliferation. VIP regulates both neuronal survival and cell division (2). A system whereby labeled VIP is suggested as a tumor marker has been proposed, localizing in vivo tumors of patients with gastrointestinal neuroendocrine cancers as well as pancreatic and colonic adenocarcinomas (4). Other studies have identified a very high incidence of VIP receptor binding in breast, ovarian, endometrial, prostate, bladder, lung, esophageal, colonic, and pancreatic tumors as well as in neuroendocrine and brain tumors (5). However, the VIP effect on cancer growth depends on the specific tumor and may be stimulatory (6, 7) or inhibitory (8). In view of the high incidence of tumors containing VIP receptors, a potential intervention in tumor growth may employ a gene downstr...

show abstract

Expression of TGF-beta related Smad proteins in human epithelial skin tumors.

Cited by 26 publications

References 0 publications

Long-term expansion of human functional epidermal precursor cells: promotion of extensive amplification by low TGF-β1 concentrations

Long-term expansion of human functional epidermal precursor cells: promotion of extensive amplification by low TGF-β1 concentrations

Targeted Disruption of Smad4 in Mouse Epidermis Results in Failure of Hair Follicle Cycling and Formation of Skin Tumors

Cloning and Characterization of the Human Activity-dependent Neuroprotective Protein

Contact Info

Product

Resources

About