Scatter factor/hepatocyte growth factor as a regulator of skeletal muscle and neural crest development.

Takayama, Hisashi; Rochelle, W J La; Anver, Miriam R.; Bockman, Dale E.; Merlino, Glenn

doi:10.1073/pnas.93.12.5866

Cited by 178 publications

(164 citation statements)

References 31 publications

(21 reference statements)

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“…Lack of HGF, as shown by gene knock-out studies in mice, results in improper ontogeny of several organs including the placenta, liver and muscle leading to inutero/utero demise (Schmidt et al, 1995;Uehara et al, 1995). Overexpression of HGF in transgenic mice, on the other hand, is accompanied by an abnormal migration and di erentiation of skeletal muscle and neural crest progenitor cells during embryonic development (Takayama et al, 1996). These ®ndings highlight that proper expression of HGF is essential for normal tissue growth and di erentiation.…”

Section: Introductionmentioning

confidence: 91%

Transcriptional regulation of the hepatocyte growth factor (HGF) gene by the Sp family of transcription factors

et al. 1997

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In this study, we have localized an enhancer element in the 5'-¯anking region of the HGF gene promoter and have identi®ed its functional transcriptional factors. Through transient transfection of NIH3T3 ®broblast cells and gel mobility shift assays, the functional binding site was localized to a short region (7318 to 7303 bp from the transcription start site) which has a CTCCC sequence. This motif is also conserved in the human HGF promoter and acts as a binding site for the Sp family of transcription factors. In the presence of NIH3T3 nuclear protein extracts, this enhancer region formed speci®c DNA-protein complexes which were totally abrogated by excess amounts of consensus Sp1 oligonucleotide. In gel mobility supershift assays, antiSp1 and anti-Sp3 antibodies speci®cally recognized these complexes as was evident by their slower migration. Sitespeci®c mutation of this binding motif resulted in total loss of Sp1 and Sp3 binding and a concomitant loss of enhancer function within the context of the HGF promoter. Furthermore, in transient cotransfection assays, overexpression of Sp1 and/or Sp3 stimulated HGF promoter activity independently and additively through binding to the Sp1 binding site in the HGF gene promoter region. DNaseI hypersensitive analysis of freshly isolated nuclei from NIH3T3 cells revealed that ®ve hypersensitive sites (HSS) are present within the 2 kb region immediately upstream of the HGF promoter. One of these sites was mapped to position 70.3 kb from the transcription start site. These data show that both Sp1 and Sp3 transcription factors upregulate HGF promoter activity by binding to the Sp1 binding site at position 7318 to 7303 bp in the HGF gene promoter.

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Section: Introductionmentioning

confidence: 91%

Transcriptional regulation of the hepatocyte growth factor (HGF) gene by the Sp family of transcription factors

et al. 1997

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“…Moreover, HGF has recently been described as a migratory factor in development: In c-met and HGF -/-mice, migration of myogenic precursor cells into the limb anlagen is abolished (Bladt et al, 1995). Inappropriate expression of HGF in transgenic mice results in abnormal skeletal muscle formation and melanosis in the nervous system, indicating that HGF induces migration of myogenic or neural crest-derived cells to ectopic sites (Takayama et al, 1996). An involvement of c-erbB2 in metastasis has been suggested by a variety of clinical data (cf.…”

Section: Discussionmentioning

confidence: 99%

Role of morphogenetic factors in metastasis of mammary carcinoma cells

et al. 1998

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We have analysed the role of the morphogenetic factors hepatocyte growth factor/scatter factor (HGF), neuregulin and E-cadherin in the process of metastasis and morphogenesis of mammary carcinoma cells. The cDNAs for HGF, neuregulin and E-cadherin were stably expressed in anaplastic human MDA MB 435 carcinoma cells. The altered cells were then injected into the mammary fat pads of nude mice, where they form tumors which can spontaneously metastasize to the lungs. We found that expression of HGF or neuregulin promoted metastasis whereas expression of the cell adhesion molecule E-cadherin was inhibitory. Moreover, expression of E-cadherin reconstituted the ability of the cells to form morphogenetic structures in matrigel cultures in response to HGF. These data demonstrate that HGF and neuregulin, which control branching or lobulo-alveolar morphogenesis of normal breast epithelium, do have metastasis-promoting eects on breast carcinoma cells. Moreover, our results suggest that the dierential activities of the two factors can be explained by the degree of epithelial dierentiation: induction of morphogenesis requires an intact epithelial adhesion and dierentiation system, whereas induction of metastasis is observed when the cells have lost their epithelial characteristics.

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“…They traverse discrete stages of differentiation recognizable in terms of marker expression, ultimately populating the basal epidermis as well as the hair follicle in human. In certain furry mammals such as the rodents, the epidermal population may be transient, a feature likely arising from a lack of SCF expression by basal keratinocytes since persistent epidermal melanocytes have been observed in transgenic mice, which ubiquitously express the cytokine HGF (Takayama et al 1996) or keratinocyte-targeted SCF (Kunisada et al 1998). Within hair follicles, melanocytes reside in two locations: at the bulb (where they function as differentiated cells to provide pigment to the growing hair matrix) and as stem cells within the bulge region, located at the base of the permanent portion of the follicle .…”

Section: Melanocyte Stem Cellsmentioning

confidence: 99%

Malignant melanoma: genetics and therapeutics in the genomic era

2006

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Cell for cell, probably no human cancer is as aggressive as melanoma. It is among a handful of cancers whose dimensions are reported in millimeters. Tumor thickness approaching 4 mm presents a high risk of metastasis, and a diagnosis of metastatic melanoma carries with it an abysmal median survival of 6-9 mo. What features of this malignancy account for such aggressive behavior? Is it the migratory history of its cell of origin or the programmed adaptation of its differentiated progeny to environmental stress, particularly ultraviolet radiation? While the answers to these questions are far from complete, major strides have been made in our understanding of the cellular, molecular, and genetic underpinnings of melanoma. More importantly, these discoveries carry profound implications for the development of therapies focused directly at the molecular engines driving melanoma, suggesting that we may have reached the brink of an unprecedented opportunity to translate basic science into clinical advances. In this review, we attempt to summarize our current understanding of the genetics and biology of this disease, drawing from expanding genomic information and lessons from development and genetically engineered mouse models. In addition, we look forward toward how these new insights will impact on therapeutic options for metastatic melanoma in the near future. The diseaseMelanomas most often arise within epidermal melanocytes of the skin, although they can also derive from noncutaneous melanocytes such as those lining the choroidal layer of the eye, GI and GU mucosal surfaces, or the meninges. Melanoma is also among the more common causes of "metastatic cancer of unknown primary," which may reflect either a propensity to arise in unexpected sites along the neural crest migratory route, or rapid growth of poorly differentiated lesions arising from indolent or unrecognized cutaneous primary lesions. Clinical staging for primary cutaneous melanoma employs measurements of thickness (in millimeters), presence of ulceration, penetration through cutaneous layers, mitotic rate, evidence of "in transit" metastasis, tumor spread to draining lymph nodes, and evidence of distant metastasis. Management issues in melanoma can be classified in terms of prevention, diagnosis, local disease management, and treatment of metastatic disease.In view of the epidemiological and emerging experimental evidence linking melanoma incidence to UV exposure and skin phototype, prevention and screening strategies represent key areas for reduction of disease incidence and severity. For most cutaneous melanomas in the so-called radial growth phase (e.g., thin melanomas), surgical removal affords curative treatment. In contrast, a significant fraction of patients diagnosed with intermediate-thickness (2-4 mm) cutaneous melanoma eventually succumb to recurrence at regional or distant sites.Critical biological questions facing the melanoma research community include: (1) What genetic and environmental factors contribute to and/or modulate risk of melanom...

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Scatter factor/hepatocyte growth factor as a regulator of skeletal muscle and neural crest development.

Cited by 178 publications

References 31 publications

Transcriptional regulation of the hepatocyte growth factor (HGF) gene by the Sp family of transcription factors

Transcriptional regulation of the hepatocyte growth factor (HGF) gene by the Sp family of transcription factors

Role of morphogenetic factors in metastasis of mammary carcinoma cells

Malignant melanoma: genetics and therapeutics in the genomic era

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