Glucocorticoids have inhibitory effects on the proliferation of several cell types. In this study... more Glucocorticoids have inhibitory effects on the proliferation of several cell types. In this study, we found that dexamethasone, a synthetic steroid with glucocorticoid activity, inhibits proliferation of established mouse Pam 212 keratinocytes. Transfection with the adenoviral early region 1a (E1a) gene confers a strong resistance to the inhibition by dexamethasone. Two deletion E1a mutants, one whose product lacks the ability to bind the cellular proteins p60/p105/p107 and another that is unable to bind p300, were shown to induce a resistance similar to that associated with the intact E1a gene. These results differ from those previously observed with two other growth inhibitory signals, transforming growth factor beta 1 and adenosine 3',5'-cyclic monophosphate, in which the mutated E1a genes confer only partial or no resistance, indicating that a different mechanism mediates resistance against glucocorticoids.
Glucocorticoids have inhibitory effects on the proliferation of several cell types. In this study... more Glucocorticoids have inhibitory effects on the proliferation of several cell types. In this study, we found that dexamethasone, a synthetic steroid with glucocorticoid activity, inhibits proliferation of established mouse Pam 212 keratinocytes. Transfection with the adenoviral early region 1a (E1a) gene confers a strong resistance to the inhibition by dexamethasone. Two deletion E1a mutants, one whose product lacks the ability to bind the cellular proteins p60/p105/p107 and another that is unable to bind p300, were shown to induce a resistance similar to that associated with the intact E1a gene. These results differ from those previously observed with two other growth inhibitory signals, transforming growth factor beta 1 and adenosine 3',5'-cyclic monophosphate, in which the mutated E1a genes confer only partial or no resistance, indicating that a different mechanism mediates resistance against glucocorticoids.
Glucocorticoids have inhibitory effects on the proliferation of several cell types. In this study... more Glucocorticoids have inhibitory effects on the proliferation of several cell types. In this study, we found that dexamethasone, a synthetic steroid with glucocorticoid activity, inhibits proliferation of established mouse Pam 212 keratinocytes. Transfection with the adenoviral early region 1a (E1a) gene confers a strong resistance to the inhibition by dexamethasone. Two deletion E1a mutants, one whose product lacks the ability to bind the cellular proteins p60/p105/p107 and another that is unable to bind p300, were shown to induce a resistance similar to that associated with the intact E1a gene. These results differ from those previously observed with two other growth inhibitory signals, transforming growth factor beta 1 and adenosine 3',5'-cyclic monophosphate, in which the mutated E1a genes confer only partial or no resistance, indicating that a different mechanism mediates resistance against glucocorticoids.
Hamlet's question is the artist's expression of the meaning of life. The second law of th... more Hamlet's question is the artist's expression of the meaning of life. The second law of thermodynamics is the physicist's equivalent
The bacteriophage fl genome contains an intergenic region (IG) 508 nucleotides long that does not... more The bacteriophage fl genome contains an intergenic region (IG) 508 nucleotides long that does not code for any known protein. By using chimeric plasmids harboring different portions of this region as well as neighboring parts of the fl genome, we have identified three functional ...
Human cells produce thousands of lipids that change during cell differentiation and can vary acro... more Human cells produce thousands of lipids that change during cell differentiation and can vary across individual cells of the same type. However, we are only starting to characterize the function of these cell-to-cell differences in lipid composition. Here, we measured the lipidomes and transcriptomes of individual human dermal fibroblasts by coupling high-resolution mass spectrometry imaging with single-cell transcriptomics. We found that the cell-to-cell variations of specific lipid metabolic pathways contribute to the establishment of cell states involved in the organization of skin architecture. Sphingolipid composition is shown to define fibroblast subpopulations, with sphingolipid metabolic rewiring driving cell-state transitions. Therefore, cell-to-cell lipid heterogeneity affects the determination of cell states, adding a new regulatory component to the self-organization of multicellular systems.
L'invention porte sur le mecanisme d'action de transduction du signal Notch qui a ete ide... more L'invention porte sur le mecanisme d'action de transduction du signal Notch qui a ete identifie comme cible dans des methodes de recherche systematique et de traitement utilisees dans la prevention et/ou la reduction de lesions cutanees induites a court et long terme par les rayons UVB, par exemple, la prevention et/ou la reduction des rides induites par les rayons UVB. L'invention porte egalement sur des methodes de recherche systematique et de traitement utilisees dans la prevention ou la reduction de lesions cutanees induites par les rayons UVB, ainsi que sur des compositions correspondantes telles que des compositions cosmetiques.
Proceedings of the National Academy of Sciences, 1994
Gap junctional communication provides a mechanism for regulating multicellular activities by allo... more Gap junctional communication provides a mechanism for regulating multicellular activities by allowing the exchange of small diffusible molecules between neighboring cells. The diversity of gap junction proteins may exist to form channels that have different permeability properties. We report here that induction of terminal differentiation in mouse primary keratinocytes by calcium results in a specific switch in gap junction protein expression. Expression of alpha 1 (connexin 43) and beta 2 (connexin 26) gap junction proteins is down-modulated, whereas that of beta 3 (connexin 31) and beta 4 (connexin 31.1) proteins is induced. Although both proliferating and differentiating keratinocytes are electrically coupled, there are significant changes in the permeability properties of the junctions to small molecules. In parallel with the changes in gap junction protein expression during differentiation, the intercellular transfer of the small dyes neurobiotin, carboxyfluorescein, and Lucife...
Proceedings of the National Academy of Sciences, 2006
Wnt and Notch signaling have long been established as strongly oncogenic in the mouse mammary gla... more Wnt and Notch signaling have long been established as strongly oncogenic in the mouse mammary gland. Aberrant expression of several Wnts and other components of this pathway in human breast carcinomas has been reported, but evidence for a causative role in the human disease has been missing. Here we report that increased Wnt signaling, as achieved by ectopic expression of Wnt-1, triggers the DNA damage response (DDR) and an ensuing cascade of events resulting in tumorigenic conversion of primary human mammary epithelial cells. Wnt-1-transformed cells have high telomerase activity and compromised p53 and Rb function, grow as spheres in suspension, and in mice form tumors that closely resemble medullary carcinomas of the breast. Notch signaling is up-regulated through a mechanism involving increased expression of the Notch ligands Dll1, Dll3, and Dll4 and is required for expression of the tumorigenic phenotype. Increased Notch signaling in primary human mammary epithelial cells is suf...
p21Cip1/WAF1 was the first cyclin-dependent kinase (CDK) inhibitor to be identified, as a mediato... more p21Cip1/WAF1 was the first cyclin-dependent kinase (CDK) inhibitor to be identified, as a mediator of p53 in DNA damage-induced growth arrest, cell senescence, and direct CDK regulation. p21 may also play an important role in differentiation-associated growth arrest, as its expression is augmented in many terminally differentiating cells. A general involvement of p21 in growth/differentiation control and tumor suppression has been questioned, as mice lacking p21 undergo a normal development, harbor no gross alterations in any of their organs, and exhibit no increase in spontaneous tumor development. However, a significant imbalance between growth and differentiation could be unmasked under conditions where normal homeostatic mechanisms are impaired. We report here that primary keratinocytes derived from p21 knockout mice, transformed with a ras oncogene, and injected subcutaneously into nude mice exhibit a very aggressive tumorigenic behavior, which is not observed with wild-type co...
Epithelial–mesenchymal interactions are key to skin morphogenesis and homeostasis. We report that... more Epithelial–mesenchymal interactions are key to skin morphogenesis and homeostasis. We report that maintenance of the hair follicle keratinocyte cell fate is defective in mice with mesenchymal deletion of the CSL/RBP-Jκ gene, the effector of “canonical” Notch signaling. Hair follicle reconstitution assays demonstrate that this can be attributed to an intrinsic defect of dermal papilla cells. Similar consequences on hair follicle differentiation result from deletion of Wnt5a, a specific dermal papilla signature gene that we found to be under direct Notch/CSL control in these cells. Functional rescue experiments establish Wnt5a as an essential downstream mediator of Notch–CSL signaling, impinging on expression in the keratinocyte compartment of FoxN1, a gene with a key hair follicle regulatory function. Thus, Notch/CSL signaling plays a unique function in control of hair follicle differentiation by the underlying mesenchyme, with Wnt5a signaling and FoxN1 as mediators.
Glucocorticoids have inhibitory effects on the proliferation of several cell types. In this study... more Glucocorticoids have inhibitory effects on the proliferation of several cell types. In this study, we found that dexamethasone, a synthetic steroid with glucocorticoid activity, inhibits proliferation of established mouse Pam 212 keratinocytes. Transfection with the adenoviral early region 1a (E1a) gene confers a strong resistance to the inhibition by dexamethasone. Two deletion E1a mutants, one whose product lacks the ability to bind the cellular proteins p60/p105/p107 and another that is unable to bind p300, were shown to induce a resistance similar to that associated with the intact E1a gene. These results differ from those previously observed with two other growth inhibitory signals, transforming growth factor beta 1 and adenosine 3',5'-cyclic monophosphate, in which the mutated E1a genes confer only partial or no resistance, indicating that a different mechanism mediates resistance against glucocorticoids.
Glucocorticoids have inhibitory effects on the proliferation of several cell types. In this study... more Glucocorticoids have inhibitory effects on the proliferation of several cell types. In this study, we found that dexamethasone, a synthetic steroid with glucocorticoid activity, inhibits proliferation of established mouse Pam 212 keratinocytes. Transfection with the adenoviral early region 1a (E1a) gene confers a strong resistance to the inhibition by dexamethasone. Two deletion E1a mutants, one whose product lacks the ability to bind the cellular proteins p60/p105/p107 and another that is unable to bind p300, were shown to induce a resistance similar to that associated with the intact E1a gene. These results differ from those previously observed with two other growth inhibitory signals, transforming growth factor beta 1 and adenosine 3',5'-cyclic monophosphate, in which the mutated E1a genes confer only partial or no resistance, indicating that a different mechanism mediates resistance against glucocorticoids.
Glucocorticoids have inhibitory effects on the proliferation of several cell types. In this study... more Glucocorticoids have inhibitory effects on the proliferation of several cell types. In this study, we found that dexamethasone, a synthetic steroid with glucocorticoid activity, inhibits proliferation of established mouse Pam 212 keratinocytes. Transfection with the adenoviral early region 1a (E1a) gene confers a strong resistance to the inhibition by dexamethasone. Two deletion E1a mutants, one whose product lacks the ability to bind the cellular proteins p60/p105/p107 and another that is unable to bind p300, were shown to induce a resistance similar to that associated with the intact E1a gene. These results differ from those previously observed with two other growth inhibitory signals, transforming growth factor beta 1 and adenosine 3',5'-cyclic monophosphate, in which the mutated E1a genes confer only partial or no resistance, indicating that a different mechanism mediates resistance against glucocorticoids.
Hamlet's question is the artist's expression of the meaning of life. The second law of th... more Hamlet's question is the artist's expression of the meaning of life. The second law of thermodynamics is the physicist's equivalent
The bacteriophage fl genome contains an intergenic region (IG) 508 nucleotides long that does not... more The bacteriophage fl genome contains an intergenic region (IG) 508 nucleotides long that does not code for any known protein. By using chimeric plasmids harboring different portions of this region as well as neighboring parts of the fl genome, we have identified three functional ...
Human cells produce thousands of lipids that change during cell differentiation and can vary acro... more Human cells produce thousands of lipids that change during cell differentiation and can vary across individual cells of the same type. However, we are only starting to characterize the function of these cell-to-cell differences in lipid composition. Here, we measured the lipidomes and transcriptomes of individual human dermal fibroblasts by coupling high-resolution mass spectrometry imaging with single-cell transcriptomics. We found that the cell-to-cell variations of specific lipid metabolic pathways contribute to the establishment of cell states involved in the organization of skin architecture. Sphingolipid composition is shown to define fibroblast subpopulations, with sphingolipid metabolic rewiring driving cell-state transitions. Therefore, cell-to-cell lipid heterogeneity affects the determination of cell states, adding a new regulatory component to the self-organization of multicellular systems.
L'invention porte sur le mecanisme d'action de transduction du signal Notch qui a ete ide... more L'invention porte sur le mecanisme d'action de transduction du signal Notch qui a ete identifie comme cible dans des methodes de recherche systematique et de traitement utilisees dans la prevention et/ou la reduction de lesions cutanees induites a court et long terme par les rayons UVB, par exemple, la prevention et/ou la reduction des rides induites par les rayons UVB. L'invention porte egalement sur des methodes de recherche systematique et de traitement utilisees dans la prevention ou la reduction de lesions cutanees induites par les rayons UVB, ainsi que sur des compositions correspondantes telles que des compositions cosmetiques.
Proceedings of the National Academy of Sciences, 1994
Gap junctional communication provides a mechanism for regulating multicellular activities by allo... more Gap junctional communication provides a mechanism for regulating multicellular activities by allowing the exchange of small diffusible molecules between neighboring cells. The diversity of gap junction proteins may exist to form channels that have different permeability properties. We report here that induction of terminal differentiation in mouse primary keratinocytes by calcium results in a specific switch in gap junction protein expression. Expression of alpha 1 (connexin 43) and beta 2 (connexin 26) gap junction proteins is down-modulated, whereas that of beta 3 (connexin 31) and beta 4 (connexin 31.1) proteins is induced. Although both proliferating and differentiating keratinocytes are electrically coupled, there are significant changes in the permeability properties of the junctions to small molecules. In parallel with the changes in gap junction protein expression during differentiation, the intercellular transfer of the small dyes neurobiotin, carboxyfluorescein, and Lucife...
Proceedings of the National Academy of Sciences, 2006
Wnt and Notch signaling have long been established as strongly oncogenic in the mouse mammary gla... more Wnt and Notch signaling have long been established as strongly oncogenic in the mouse mammary gland. Aberrant expression of several Wnts and other components of this pathway in human breast carcinomas has been reported, but evidence for a causative role in the human disease has been missing. Here we report that increased Wnt signaling, as achieved by ectopic expression of Wnt-1, triggers the DNA damage response (DDR) and an ensuing cascade of events resulting in tumorigenic conversion of primary human mammary epithelial cells. Wnt-1-transformed cells have high telomerase activity and compromised p53 and Rb function, grow as spheres in suspension, and in mice form tumors that closely resemble medullary carcinomas of the breast. Notch signaling is up-regulated through a mechanism involving increased expression of the Notch ligands Dll1, Dll3, and Dll4 and is required for expression of the tumorigenic phenotype. Increased Notch signaling in primary human mammary epithelial cells is suf...
p21Cip1/WAF1 was the first cyclin-dependent kinase (CDK) inhibitor to be identified, as a mediato... more p21Cip1/WAF1 was the first cyclin-dependent kinase (CDK) inhibitor to be identified, as a mediator of p53 in DNA damage-induced growth arrest, cell senescence, and direct CDK regulation. p21 may also play an important role in differentiation-associated growth arrest, as its expression is augmented in many terminally differentiating cells. A general involvement of p21 in growth/differentiation control and tumor suppression has been questioned, as mice lacking p21 undergo a normal development, harbor no gross alterations in any of their organs, and exhibit no increase in spontaneous tumor development. However, a significant imbalance between growth and differentiation could be unmasked under conditions where normal homeostatic mechanisms are impaired. We report here that primary keratinocytes derived from p21 knockout mice, transformed with a ras oncogene, and injected subcutaneously into nude mice exhibit a very aggressive tumorigenic behavior, which is not observed with wild-type co...
Epithelial–mesenchymal interactions are key to skin morphogenesis and homeostasis. We report that... more Epithelial–mesenchymal interactions are key to skin morphogenesis and homeostasis. We report that maintenance of the hair follicle keratinocyte cell fate is defective in mice with mesenchymal deletion of the CSL/RBP-Jκ gene, the effector of “canonical” Notch signaling. Hair follicle reconstitution assays demonstrate that this can be attributed to an intrinsic defect of dermal papilla cells. Similar consequences on hair follicle differentiation result from deletion of Wnt5a, a specific dermal papilla signature gene that we found to be under direct Notch/CSL control in these cells. Functional rescue experiments establish Wnt5a as an essential downstream mediator of Notch–CSL signaling, impinging on expression in the keratinocyte compartment of FoxN1, a gene with a key hair follicle regulatory function. Thus, Notch/CSL signaling plays a unique function in control of hair follicle differentiation by the underlying mesenchyme, with Wnt5a signaling and FoxN1 as mediators.
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