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Marcel F Jonkman - One of the best experts on this subject based on the ideXlab platform.
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induced pluripotent stem cells from human Revertant keratinocytes for the treatment of epidermolysis bullosa
Science Translational Medicine, 2014Co-Authors: Noriko Umegakiarao, Marcel F Jonkman, A Gostynski, Anna M G Pasmooij, Munenari Itoh, Jane E Cerise, Brynn Levy, Lisa Rothman, Angela M ChristianoAbstract:Revertant mosaicism is a naturally occurring phenomenon involving spontaneous correction of a pathogenic gene mutation in a somatic cell. It has been observed in several genetic diseases, including epidermolysis bullosa (EB), a group of inherited skin disorders characterized by blistering and scarring. Induced pluripotent stem cells (iPSCs), generated from fibroblasts or keratinocytes, have been proposed as a treatment for EB. However, this requires genome editing to correct the mutations, and, in gene therapy, efficiency of targeted gene correction and deleterious genomic modifications are still limitations of translation. We demonstrate the generation of iPSCs from Revertant keratinocytes of a junctional EB patient with compound heterozygous COL17A1 mutations. These Revertant iPSCs were then differentiated into naturally genetically corrected keratinocytes that expressed type XVII collagen (Col17). Gene expression profiling showed a strong correlation between gene expression in Revertant iPSC–derived keratinocytes and the original Revertant keratinocytes, indicating the successful differentiation of iPSCs into the keratinocyte lineage. Revertant-iPSC keratinocytes were then used to create in vitro three-dimensional skin equivalents and reconstitute human skin in vivo in mice, both of which expressed Col17 in the basal layer. Therefore, Revertant keratinocytes may be a viable source of spontaneously gene-corrected cells for developing iPSC-based therapeutic approaches in EB.
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successful therapeutic transplantation of Revertant skin in epidermolysis bullosa
Journal of The American Academy of Dermatology, 2014Co-Authors: A Gostynski, Anna M G Pasmooij, Marcel F JonkmanAbstract:Background Epidermolysis bullosa (EB) is a group of genetic blistering diseases. Despite many efforts, treatment for EB remains symptomatic. Revertant mosaicism, coexistence of cells carrying disease-causing mutations with cells in which the inherited mutation is genetically corrected by a spontaneous genetic event (Revertant cells) in 1 individual, can be found in EB. The naturally corrected Revertant keratinocytes provide an opportunity for autologous cell therapy. Objective We sought to locally treat EB by transplantation of Revertant skin. Methods Persistent ulcers in a patient with non-Herlitz junctional EB caused by mutations in the LAMB3 gene were treated by transplantation of split-thickness biopsy specimens from one of his Revertant patches. Results All transplanted biopsy specimens were accepted and complete re-epithelialization occurred within 14 days. During 18 months of follow-up, the patient never experienced blisters or wounds in the grafted area, nor in the healed donor site. Immunofluorescence and DNA sequencing showed that acceptor sites healed with transplanted Revertant keratinocytes. Limitations Punch grafting allows only limited expansion of Revertant skin. Conclusions We demonstrate that phenotypical and genotypical correction of skin in patients with Revertant mosaicism by expansion of Revertant skin might be a promising therapeutic option for cutaneous manifestations of EB.
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Revertant mosaicism in heritable skin diseases mechanisms of natural gene therapy
Discovery Medicine, 2012Co-Authors: Anna M G Pasmooij, Marcel F Jonkman, Jouni UittoAbstract:Revertant mosaicism (RM) refers to the co-existence of cells carrying disease-causing mutations with cells in which the inherited mutation is genetically corrected by a spontaneous event. It has been discovered in an increasing number of heritable skin diseases: ichthyosis with confetti and different subtypes of epidermolysis bullosa. This "natural gene therapy" phenomenon manifests as normal appearing skin areas surrounded by affected skin. Although initially thought to be rare, RM is now considered relatively common in genetic skin diseases. To address the issues relevant to RM, we here discuss the following questions: 1) What is the incidence of RM in heritable skin diseases? 2) What are the repair mechanisms in RM? 3) When do the Revertant mutations occur? 4) How do you recognize Revertant skin? 5) Do the areas of RM change in size? The answers to these questions allow us to acquire knowledge on these reverted cells, the mechanisms of RM, and utility of the reverted cells to the advantage of the patient. The Revertant skin could potentially be used to treat the patient's own affected skin.
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Revertant mosaicism in a human skin fragility disorder results from slipped mispairing and mitotic recombination
Journal of Clinical Investigation, 2012Co-Authors: Dimitra Kiritsi, Marcel F Jonkman, Anna M G Pasmooij, Meltem Onder, Rudolf Happle, Leena Brucknertuderman, Cristina HasAbstract:Spontaneous gene repair, also called Revertant mosaicism, has been documented in several genetic disorders involving organs that undergo self-regeneration, including the skin. Genetic reversion may occur through different mechanisms, and in a single individual, the mutation can be repaired in various ways. Here we describe a disseminated pattern of Revertant mosaicism observed in 6 patients with Kindler syndrome (KS), a genodermatosis caused by loss of kindlin-1 (encoded by FERMT1) and clinically characterized by patchy skin pigmentation and atrophy. All patients presented duplication mutations (c.456dupA and c.676dupC) in FERMT1, and slipped mispairing in direct nucleotide repeats was identified as the reversion mechanism in all investigated Revertant skin spots. The sequence around the mutations demonstrated high propensity to mutations, favoring both microinsertions and microdeletions. Additionally, in some Revertant patches, mitotic recombination generated areas with homozygous normal keratinocytes. Restoration of kindlin-1 expression led to clinically and structurally normal skin. Since loss of kindlin-1 severely impairs keratinocyte proliferation, we predict that Revertant cells have a selective advantage that allows their clonal expansion and, consequently, the improvement of the skin condition.
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Revertant mosaicism due to a second site mutation in col7a1 in a patient with recessive dystrophic epidermolysis bullosa
Journal of Investigative Dermatology, 2010Co-Authors: Anna M G Pasmooij, Marcel F Jonkman, Marta Garcia, Maria Jose Escamez, Miranda A Nijenhuis, Antoni Azon, N Cuadradocorrales, Marcela Del RioAbstract:Despite the high incidence of Revertant mosaicism (35%) in patients with the genetic skin disease epidermolysis bullosa (EB) due to correcting mutations in the genes COL17A1 and LAMB3, Revertant mosaicism has not been described for COL7A1 until recently. Mutations in COL7A1 are responsible for the most devastating form of EB in adults, which is characterized by cocooned "mitten" deformities of the hands. This report shows in vivo reversion of an inherited COL7A1 mutation in a patient with recessive dystrophic EB who was homozygous for the frameshift mutation COL7A1:c.6527insC,p.2176FsX337. The patient exhibited a patch of clinically healthy Revertant skin on her left forearm. The second-site mutation c.6528delT, which is present in Revertant keratinocytes, resulted in correction of the reading frame. As the new CCC codon codes for the same amino acid proline as the wild-type codon CCT, the Revertant cells expressed wild-type type VII collagen polypeptide, leading to restoration of skin function. We hypothesize that, on careful examination, Revertant mosaicism might be found to be more common in patients with type VII collagen-deficient EB. Furthermore, the Revertant keratinocytes might offer the possibility to explore cell-based therapeutic strategies, by culturing in vitro and subsequently grafting as part of bioengineered dermo-epidermal substitutes on affected skin.
P Lengyel - One of the best experts on this subject based on the ideXlab platform.
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recessive mediator Revertants from c h ras oncogene transformed nih 3t3 cells tumorigenicity in nude mice and transient anchorage and serum independence of the recovered tumor cells in culture
Journal of Cellular Physiology, 1991Co-Authors: T Omatayamada, Hisafumi Yamada, P LengyelAbstract:We have reported earlier the isolation of two recessive, serum- and anchoragedependent Revertants (R116 and R260) from a c-H-ras oncogene-transformed NIH 3T3 line. In both Revertants, the oncogene was fully expressed and fusion of either Revertant with (untransformed) NIH 3T3 cells, or of the two Revertants with one another, resulted in transformed progeny. These, and other data, indicated that the transforming activity of the oncogene was impaired in the two Revertants in consequence of defects in distinct genes needed to mediate this activity. We report here that neither Revertant could be re-transformed by the K-ras or N-ras oncogene (though they could be re-transformed by several other oncogenes). The two Revertants turned out to be tumorigenic in nude mice (though less so than the parental transformed cells). The tumor cells, as recovered, formed foci and had a transformed morphology and a greatly diminished serum and anchorage dependence. Growth of the cells in culture (for 20 passages) resulted in their regaining the characteristics (i.e., anchorage and serum dependence) of cultured R116 and R260 cells. Proliferation of the cells in nude mice was not accompanied by a change in the level of ras oncogene expression or in gene amplification, at least as manifested in the lack of appearance of double-minute chromosomes. The addition of the growth factors TGF alpha and beta to the medium of either Revertant did not support anchorage-independent growth.
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characterization of recessive mediator Revertants from nih 3t3 cells transformed with a c h ras oncogene
Journal of Biological Chemistry, 1991Co-Authors: Hisafumi Yamada, T Omatayamada, P LengyelAbstract:We have reported earlier the isolation of two recessive, serum- and anchorage-dependent Revertants from an NIH 3T3 line which had been transformed with multiple copies of a c-H-ras oncogene. In both Revertants the oncogene was fully expressed and fusion of either Revertant with normal (untransformed) cells or of the two Revertants with one another resulted in transformed progeny. These, and other data indicate that the transforming activity of the c-H-ras oncogene is impaired in the two Revertants, in consequence of defects in distinct genes needed to mediate this activity. Here, we describe some of the biochemical features of the Revertants. In both of these (as in the transformed line) the bulk of the ras-p21 protein was found in the membrane fraction. This suggests proper posttranslational processing. Furthermore, no difference was detected either in the ras-p21 protein GTPase stimulating activity of GAP or in the extent of GAP-tyrosine phosphorylation among growing cultures of the two Revertants, the transformed line and the parental NIH 3T3 line. The level of glucose transporter mRNA was severalfold higher in the transformed line than in the NIH 3T3 line. In the two Revertants, however, the level was as low as that in the NIH 3T3 line. This indicates that the reversion impaired the effect of the c-H-ras oncogene on transcription. The raf oncogene (proposed to increase transcription factor activity) could retransform both Revertants. Moreover, as revealed in experiments with growing cultures, neither transformation by the c-H-ras oncogene nor reversion from the transformed state altered the electrophoretic mobility of the raf protein or the level of its actin kinase activity. These results suggest that transformation by the c-H-ras oncogene is not mediated by the activation of raf protein kinase. The tyrosine phosphorylation of the p34cdc2 protein kinase (a cell cycle regulatory enzyme) was severalfold higher in the transformed line than in the NIH 3T3 line. The level of p34cdc2 protein kinase phosphorylation was as high in the R260 Revertant as in the transformed line and as low in the R116 Revertant as in the NIH 3T3 line. We are attempting to identify the defective mediator genes impairing the transforming activity of the c-H-ras oncogene in the two Revertants.
Anna M G Pasmooij - One of the best experts on this subject based on the ideXlab platform.
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induced pluripotent stem cells from human Revertant keratinocytes for the treatment of epidermolysis bullosa
Science Translational Medicine, 2014Co-Authors: Noriko Umegakiarao, Marcel F Jonkman, A Gostynski, Anna M G Pasmooij, Munenari Itoh, Jane E Cerise, Brynn Levy, Lisa Rothman, Angela M ChristianoAbstract:Revertant mosaicism is a naturally occurring phenomenon involving spontaneous correction of a pathogenic gene mutation in a somatic cell. It has been observed in several genetic diseases, including epidermolysis bullosa (EB), a group of inherited skin disorders characterized by blistering and scarring. Induced pluripotent stem cells (iPSCs), generated from fibroblasts or keratinocytes, have been proposed as a treatment for EB. However, this requires genome editing to correct the mutations, and, in gene therapy, efficiency of targeted gene correction and deleterious genomic modifications are still limitations of translation. We demonstrate the generation of iPSCs from Revertant keratinocytes of a junctional EB patient with compound heterozygous COL17A1 mutations. These Revertant iPSCs were then differentiated into naturally genetically corrected keratinocytes that expressed type XVII collagen (Col17). Gene expression profiling showed a strong correlation between gene expression in Revertant iPSC–derived keratinocytes and the original Revertant keratinocytes, indicating the successful differentiation of iPSCs into the keratinocyte lineage. Revertant-iPSC keratinocytes were then used to create in vitro three-dimensional skin equivalents and reconstitute human skin in vivo in mice, both of which expressed Col17 in the basal layer. Therefore, Revertant keratinocytes may be a viable source of spontaneously gene-corrected cells for developing iPSC-based therapeutic approaches in EB.
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successful therapeutic transplantation of Revertant skin in epidermolysis bullosa
Journal of The American Academy of Dermatology, 2014Co-Authors: A Gostynski, Anna M G Pasmooij, Marcel F JonkmanAbstract:Background Epidermolysis bullosa (EB) is a group of genetic blistering diseases. Despite many efforts, treatment for EB remains symptomatic. Revertant mosaicism, coexistence of cells carrying disease-causing mutations with cells in which the inherited mutation is genetically corrected by a spontaneous genetic event (Revertant cells) in 1 individual, can be found in EB. The naturally corrected Revertant keratinocytes provide an opportunity for autologous cell therapy. Objective We sought to locally treat EB by transplantation of Revertant skin. Methods Persistent ulcers in a patient with non-Herlitz junctional EB caused by mutations in the LAMB3 gene were treated by transplantation of split-thickness biopsy specimens from one of his Revertant patches. Results All transplanted biopsy specimens were accepted and complete re-epithelialization occurred within 14 days. During 18 months of follow-up, the patient never experienced blisters or wounds in the grafted area, nor in the healed donor site. Immunofluorescence and DNA sequencing showed that acceptor sites healed with transplanted Revertant keratinocytes. Limitations Punch grafting allows only limited expansion of Revertant skin. Conclusions We demonstrate that phenotypical and genotypical correction of skin in patients with Revertant mosaicism by expansion of Revertant skin might be a promising therapeutic option for cutaneous manifestations of EB.
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Revertant mosaicism in heritable skin diseases mechanisms of natural gene therapy
Discovery Medicine, 2012Co-Authors: Anna M G Pasmooij, Marcel F Jonkman, Jouni UittoAbstract:Revertant mosaicism (RM) refers to the co-existence of cells carrying disease-causing mutations with cells in which the inherited mutation is genetically corrected by a spontaneous event. It has been discovered in an increasing number of heritable skin diseases: ichthyosis with confetti and different subtypes of epidermolysis bullosa. This "natural gene therapy" phenomenon manifests as normal appearing skin areas surrounded by affected skin. Although initially thought to be rare, RM is now considered relatively common in genetic skin diseases. To address the issues relevant to RM, we here discuss the following questions: 1) What is the incidence of RM in heritable skin diseases? 2) What are the repair mechanisms in RM? 3) When do the Revertant mutations occur? 4) How do you recognize Revertant skin? 5) Do the areas of RM change in size? The answers to these questions allow us to acquire knowledge on these reverted cells, the mechanisms of RM, and utility of the reverted cells to the advantage of the patient. The Revertant skin could potentially be used to treat the patient's own affected skin.
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Revertant mosaicism in a human skin fragility disorder results from slipped mispairing and mitotic recombination
Journal of Clinical Investigation, 2012Co-Authors: Dimitra Kiritsi, Marcel F Jonkman, Anna M G Pasmooij, Meltem Onder, Rudolf Happle, Leena Brucknertuderman, Cristina HasAbstract:Spontaneous gene repair, also called Revertant mosaicism, has been documented in several genetic disorders involving organs that undergo self-regeneration, including the skin. Genetic reversion may occur through different mechanisms, and in a single individual, the mutation can be repaired in various ways. Here we describe a disseminated pattern of Revertant mosaicism observed in 6 patients with Kindler syndrome (KS), a genodermatosis caused by loss of kindlin-1 (encoded by FERMT1) and clinically characterized by patchy skin pigmentation and atrophy. All patients presented duplication mutations (c.456dupA and c.676dupC) in FERMT1, and slipped mispairing in direct nucleotide repeats was identified as the reversion mechanism in all investigated Revertant skin spots. The sequence around the mutations demonstrated high propensity to mutations, favoring both microinsertions and microdeletions. Additionally, in some Revertant patches, mitotic recombination generated areas with homozygous normal keratinocytes. Restoration of kindlin-1 expression led to clinically and structurally normal skin. Since loss of kindlin-1 severely impairs keratinocyte proliferation, we predict that Revertant cells have a selective advantage that allows their clonal expansion and, consequently, the improvement of the skin condition.
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Revertant mosaicism due to a second site mutation in col7a1 in a patient with recessive dystrophic epidermolysis bullosa
Journal of Investigative Dermatology, 2010Co-Authors: Anna M G Pasmooij, Marcel F Jonkman, Marta Garcia, Maria Jose Escamez, Miranda A Nijenhuis, Antoni Azon, N Cuadradocorrales, Marcela Del RioAbstract:Despite the high incidence of Revertant mosaicism (35%) in patients with the genetic skin disease epidermolysis bullosa (EB) due to correcting mutations in the genes COL17A1 and LAMB3, Revertant mosaicism has not been described for COL7A1 until recently. Mutations in COL7A1 are responsible for the most devastating form of EB in adults, which is characterized by cocooned "mitten" deformities of the hands. This report shows in vivo reversion of an inherited COL7A1 mutation in a patient with recessive dystrophic EB who was homozygous for the frameshift mutation COL7A1:c.6527insC,p.2176FsX337. The patient exhibited a patch of clinically healthy Revertant skin on her left forearm. The second-site mutation c.6528delT, which is present in Revertant keratinocytes, resulted in correction of the reading frame. As the new CCC codon codes for the same amino acid proline as the wild-type codon CCT, the Revertant cells expressed wild-type type VII collagen polypeptide, leading to restoration of skin function. We hypothesize that, on careful examination, Revertant mosaicism might be found to be more common in patients with type VII collagen-deficient EB. Furthermore, the Revertant keratinocytes might offer the possibility to explore cell-based therapeutic strategies, by culturing in vitro and subsequently grafting as part of bioengineered dermo-epidermal substitutes on affected skin.
Jouni Uitto - One of the best experts on this subject based on the ideXlab platform.
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Revertant mosaicism in heritable skin diseases mechanisms of natural gene therapy
Discovery Medicine, 2012Co-Authors: Anna M G Pasmooij, Marcel F Jonkman, Jouni UittoAbstract:Revertant mosaicism (RM) refers to the co-existence of cells carrying disease-causing mutations with cells in which the inherited mutation is genetically corrected by a spontaneous event. It has been discovered in an increasing number of heritable skin diseases: ichthyosis with confetti and different subtypes of epidermolysis bullosa. This "natural gene therapy" phenomenon manifests as normal appearing skin areas surrounded by affected skin. Although initially thought to be rare, RM is now considered relatively common in genetic skin diseases. To address the issues relevant to RM, we here discuss the following questions: 1) What is the incidence of RM in heritable skin diseases? 2) What are the repair mechanisms in RM? 3) When do the Revertant mutations occur? 4) How do you recognize Revertant skin? 5) Do the areas of RM change in size? The answers to these questions allow us to acquire knowledge on these reverted cells, the mechanisms of RM, and utility of the reverted cells to the advantage of the patient. The Revertant skin could potentially be used to treat the patient's own affected skin.
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Revertant mosaicism in skin natural gene therapy
Trends in Molecular Medicine, 2011Co-Authors: Joey Laicheong, John A. Mcgrath, Jouni UittoAbstract:Revertant mosaicism is a naturally occurring phenomenon involving spontaneous correction of a pathogenic mutation in a somatic cell. Recent studies suggest that it is not a rare event and that it could be clinically relevant to phenotypic expression and patient treatment. Indeed, Revertant cell therapy represents a potential ‘natural gene therapy' because in vivo reversion obviates the need for further genetic correction. Revertant mosaicism has been observed in several inherited conditions, including epidermolysis bullosa, a heterogeneous group of blistering skin disorders. These diseases provide a useful model for studying Revertant mosaicism because of the visual and accessible nature of skin. This overview highlights the latest developments in Revertant mosaicism and the translational implications germane to heritable skin disorders.
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Revertant mosaicism in epidermolysis bullosa caused by mitotic gene conversion
Cell, 1997Co-Authors: Marcel F Jonkman, H Scheffer, R P Stulp, Miranda Nijenhuis, K Heeres, Katsushi Owaribe, Leena Pulkkinen, Jouni UittoAbstract:Abstract Mitotic gene conversion acting as reverse mutation has not been previously demonstrated in human. We report here that the Revertant mosaicism of a compound heterozygous proband with an autosomal recessive genodermatosis, generalized atrophic benign epidermolysis bullosa, is caused by mitotic gene conversion of one of the two mutated COL17A1 alleles. Specifically, the maternal allele surrounding the mutation site on COL17A1 (1706delA) showed reversion of the mutation and loss of heterozygosity along a tract of at least 381 bp in Revertant keratinocytes derived from clinically unaffected skin patches; the paternal mutation (R1226X) remained present in all cell samples. Revertant mosaicism represents a way of natural gene therapy.
Hisafumi Yamada - One of the best experts on this subject based on the ideXlab platform.
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recessive mediator Revertants from c h ras oncogene transformed nih 3t3 cells tumorigenicity in nude mice and transient anchorage and serum independence of the recovered tumor cells in culture
Journal of Cellular Physiology, 1991Co-Authors: T Omatayamada, Hisafumi Yamada, P LengyelAbstract:We have reported earlier the isolation of two recessive, serum- and anchoragedependent Revertants (R116 and R260) from a c-H-ras oncogene-transformed NIH 3T3 line. In both Revertants, the oncogene was fully expressed and fusion of either Revertant with (untransformed) NIH 3T3 cells, or of the two Revertants with one another, resulted in transformed progeny. These, and other data, indicated that the transforming activity of the oncogene was impaired in the two Revertants in consequence of defects in distinct genes needed to mediate this activity. We report here that neither Revertant could be re-transformed by the K-ras or N-ras oncogene (though they could be re-transformed by several other oncogenes). The two Revertants turned out to be tumorigenic in nude mice (though less so than the parental transformed cells). The tumor cells, as recovered, formed foci and had a transformed morphology and a greatly diminished serum and anchorage dependence. Growth of the cells in culture (for 20 passages) resulted in their regaining the characteristics (i.e., anchorage and serum dependence) of cultured R116 and R260 cells. Proliferation of the cells in nude mice was not accompanied by a change in the level of ras oncogene expression or in gene amplification, at least as manifested in the lack of appearance of double-minute chromosomes. The addition of the growth factors TGF alpha and beta to the medium of either Revertant did not support anchorage-independent growth.
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characterization of recessive mediator Revertants from nih 3t3 cells transformed with a c h ras oncogene
Journal of Biological Chemistry, 1991Co-Authors: Hisafumi Yamada, T Omatayamada, P LengyelAbstract:We have reported earlier the isolation of two recessive, serum- and anchorage-dependent Revertants from an NIH 3T3 line which had been transformed with multiple copies of a c-H-ras oncogene. In both Revertants the oncogene was fully expressed and fusion of either Revertant with normal (untransformed) cells or of the two Revertants with one another resulted in transformed progeny. These, and other data indicate that the transforming activity of the c-H-ras oncogene is impaired in the two Revertants, in consequence of defects in distinct genes needed to mediate this activity. Here, we describe some of the biochemical features of the Revertants. In both of these (as in the transformed line) the bulk of the ras-p21 protein was found in the membrane fraction. This suggests proper posttranslational processing. Furthermore, no difference was detected either in the ras-p21 protein GTPase stimulating activity of GAP or in the extent of GAP-tyrosine phosphorylation among growing cultures of the two Revertants, the transformed line and the parental NIH 3T3 line. The level of glucose transporter mRNA was severalfold higher in the transformed line than in the NIH 3T3 line. In the two Revertants, however, the level was as low as that in the NIH 3T3 line. This indicates that the reversion impaired the effect of the c-H-ras oncogene on transcription. The raf oncogene (proposed to increase transcription factor activity) could retransform both Revertants. Moreover, as revealed in experiments with growing cultures, neither transformation by the c-H-ras oncogene nor reversion from the transformed state altered the electrophoretic mobility of the raf protein or the level of its actin kinase activity. These results suggest that transformation by the c-H-ras oncogene is not mediated by the activation of raf protein kinase. The tyrosine phosphorylation of the p34cdc2 protein kinase (a cell cycle regulatory enzyme) was severalfold higher in the transformed line than in the NIH 3T3 line. The level of p34cdc2 protein kinase phosphorylation was as high in the R260 Revertant as in the transformed line and as low in the R116 Revertant as in the NIH 3T3 line. We are attempting to identify the defective mediator genes impairing the transforming activity of the c-H-ras oncogene in the two Revertants.
