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1.
Cell ; 186(24): 5269-5289.e22, 2023 11 22.
Article in English | MEDLINE | ID: mdl-37995656

ABSTRACT

A generic level of chromatin organization generated by the interplay between cohesin and CTCF suffices to limit promiscuous interactions between regulatory elements, but a lineage-specific chromatin assembly that supersedes these constraints is required to configure the genome to guide gene expression changes that drive faithful lineage progression. Loss-of-function approaches in B cell precursors show that IKAROS assembles interactions across megabase distances in preparation for lymphoid development. Interactions emanating from IKAROS-bound enhancers override CTCF-imposed boundaries to assemble lineage-specific regulatory units built on a backbone of smaller invariant topological domains. Gain of function in epithelial cells confirms IKAROS' ability to reconfigure chromatin architecture at multiple scales. Although the compaction of the Igκ locus required for genome editing represents a function of IKAROS unique to lymphocytes, the more general function to preconfigure the genome to support lineage-specific gene expression and suppress activation of extra-lineage genes provides a paradigm for lineage restriction.


Subject(s)
Chromatin , Genome , B-Lymphocytes/metabolism , CCCTC-Binding Factor/metabolism , Chromatin/metabolism , Chromatin Assembly and Disassembly , Humans , Animals , Mice
2.
Nat Immunol ; 23(11): 1628-1643, 2022 11.
Article in English | MEDLINE | ID: mdl-36316479

ABSTRACT

T cell differentiation requires Notch1 signaling. In the present study, we show that an enhancer upstream of Notch1 active in double-negative (DN) mouse thymocytes is responsible for raising Notch1 signaling intrathymically. This enhancer is required to expand multipotent progenitors intrathymically while delaying early differentiation until lineage restrictions have been established. Early thymic progenitors lacking the enhancer show accelerated differentiation through the DN stages and increased frequency of B, innate lymphoid (IL) and natural killer (NK) cell differentiation. Transcription regulators for T cell lineage restriction and commitment are expressed normally, but IL and NK cell gene expression persists after T cell lineage commitment and T cell receptor ß VDJ recombination, Cd3 expression and ß-selection have been impaired. This Notch1 enhancer is inactive in double-positive (DP) thymocytes. Its aberrant reactivation at this stage in Ikaros mutants is required for leukemogenesis. Thus, the DN-specific Notch1 enhancer harnesses the regulatory architecture of DN and DP thymocytes to achieve carefully orchestrated changes in Notch1 signaling required for early lineage restrictions and normal T cell differentiation.


Subject(s)
Immunity, Innate , Thymocytes , Mice , Animals , Thymocytes/metabolism , Receptor, Notch1/genetics , Receptor, Notch1/metabolism , Lymphocytes/metabolism , Thymus Gland , Cell Differentiation/genetics , Cell Lineage/genetics
3.
J Immunol ; 208(12): 2613-2621, 2022 06 15.
Article in English | MEDLINE | ID: mdl-35623662

ABSTRACT

Keratinocytes, the epithelial cells of the skin, reprogram their gene expression and produce immune effector molecules when exposed to environmental and endogenous triggers of inflammation. It remains unclear how keratinocytes process physiological signals generated during skin irritation and switch from a homeostatic to an inflammatory state. In this article, we show that the stress-activated protein kinase p38α is crucial for keratinocytes to prompt changes in their transcriptome upon cytokine stimulation and drive inflammation in allergen-exposed skin. p38α serves this function by phosphorylating p63, a transcription factor essential for the lineage identity and stemness of the skin epithelium. Phosphorylation by p38α alters the activity of p63 and redeploys this developmental transcription factor to a gene expression program linked to inflammation. Genetic ablation and pharmacological inhibition of p38α or the p38α-p63 target gene product MMP13 attenuate atopic dermatitis-like disease in mice. Our study reveals an epithelial molecular pathway promoting skin inflammation and actionable through treatment with topical small-molecule therapeutics.


Subject(s)
Dermatitis, Atopic , Mitogen-Activated Protein Kinase 14/metabolism , Transcription Factors , Animals , Dermatitis, Atopic/metabolism , Inflammation/metabolism , Keratinocytes/metabolism , Mice , Phosphorylation , Transcription Factors/metabolism
4.
J Exp Med ; 217(3)2020 03 02.
Article in English | MEDLINE | ID: mdl-31834931

ABSTRACT

Keratinocytes respond to environmental signals by eliciting induction of genes that preserve skin's integrity. Here we show that the transcriptional response to stress signaling is supported by short-lived epigenetic changes. Comparison of chromatin accessibility and transcriptional changes induced by barrier disruption or by loss of the nucleosome remodeler Mi-2ß identified their striking convergence in mouse and human keratinocytes. Mi-2ß directly repressed genes induced by barrier disruption by restricting AP1-enriched promoter-distal sites, occupied by Mi-2ß and JUNB at steady state and by c-JUN after Mi-2ß depletion or stress signaling. Barrier disruption led to a modest reduction in Mi-2ß expression and a further selective reduction of Mi-2ß localization at stress response genes, possibly through competition with activated c-JUN. Consistent with a repressive role at stress response genes, genetic ablation of Mi-2ß did not prevent reestablishment of barrier integrity but was required for return to homeostasis. Thus, a competition between Mi-2ß-repressive and activating AP1 complexes may permit rapid transcriptional response to and resolution from stress signaling.


Subject(s)
Mi-2 Nucleosome Remodeling and Deacetylase Complex/metabolism , Skin/metabolism , Transcription Factor AP-1/metabolism , Animals , Cells, Cultured , Homeostasis/physiology , Humans , Keratinocytes/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , Promoter Regions, Genetic/genetics , Signal Transduction/physiology , Transcription, Genetic/genetics
5.
Nat Immunol ; 18(3): 334-343, 2017 03.
Article in English | MEDLINE | ID: mdl-28092372

ABSTRACT

Environmental challenges to epithelial cells trigger gene expression changes that elicit context-appropriate immune responses. We found that the chromatin remodeler Mi-2ß controls epidermal homeostasis by regulating the genes involved in keratinocyte and immune-cell activation to maintain an inactive state. Mi-2ß depletion resulted in rapid deployment of both a pro-inflammatory and an immunosuppressive response in the skin. A key target of Mi-2ß in keratinocytes is the pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP). Loss of TSLP receptor (TSLPR) signaling specifically in regulatory T (Treg) cells prevented their activation and permitted rapid progression from a skin pro-inflammatory response to a lethal systemic condition. Thus, in addition to their well-characterized role in pro-inflammatory responses, keratinocytes also directly support immune-suppressive responses that are critical for re-establishing organismal homeostasis.


Subject(s)
Cytokines/metabolism , DNA Helicases/metabolism , Immunoglobulins/metabolism , Keratinocytes/physiology , Receptors, Cytokine/metabolism , T-Lymphocytes, Regulatory/physiology , Animals , Cell Communication , Cells, Cultured , Chromatin Assembly and Disassembly/genetics , DNA Helicases/genetics , Immunoglobulins/genetics , Inflammation/genetics , Lymphocyte Activation/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Receptors, Cytokine/genetics , Signal Transduction/genetics , Thymic Stromal Lymphopoietin
6.
Genes Dev ; 30(17): 1971-90, 2016 09 01.
Article in English | MEDLINE | ID: mdl-27664237

ABSTRACT

IKAROS is required for the differentiation of highly proliferative pre-B-cell precursors, and loss of IKAROS function indicates poor prognosis in precursor B-cell acute lymphoblastic leukemia (B-ALL). Here we show that IKAROS regulates this developmental stage by positive and negative regulation of superenhancers with distinct lineage affiliations. IKAROS defines superenhancers at pre-B-cell differentiation genes together with B-cell master regulators such as PAX5, EBF1, and IRF4 but is required for a highly permissive chromatin environment, a function that cannot be compensated for by the other transcription factors. IKAROS is also highly enriched at inactive enhancers of genes normally expressed in stem-epithelial cells. Upon IKAROS loss, expression of pre-B-cell differentiation genes is attenuated, while a group of extralineage transcription factors that are directly repressed by IKAROS and depend on EBF1 relocalization at their enhancers for expression is induced. LHX2, LMO2, and TEAD-YAP1, normally kept separate from native B-cell transcription regulators by IKAROS, now cooperate directly with them in a de novo superenhancer network with its own feed-forward transcriptional reinforcement. Induction of de novo superenhancers antagonizes Polycomb repression and superimposes aberrant stem-epithelial cell properties in a B-cell precursor. This dual mechanism of IKAROS regulation promotes differentiation while safeguarding against a hybrid stem-epithelial-B-cell phenotype that underlies high-risk B-ALL.


Subject(s)
Cell Differentiation/genetics , Enhancer Elements, Genetic/physiology , Epithelial Cells/cytology , Gene Expression Regulation, Leukemic , Ikaros Transcription Factor/metabolism , Precursor Cell Lymphoblastic Leukemia-Lymphoma/physiopathology , Precursor Cells, B-Lymphoid/cytology , Animals , Epigenesis, Genetic , Epithelial Cells/pathology , Ikaros Transcription Factor/genetics , Mice , Polycomb-Group Proteins/genetics , Polycomb-Group Proteins/metabolism , Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics , Precursor Cells, B-Lymphoid/pathology , Transcription Factors/genetics , Transcription Factors/metabolism
7.
Nat Immunol ; 13(1): 86-94, 2011 Nov 13.
Article in English | MEDLINE | ID: mdl-22080921

ABSTRACT

Cell fate depends on the interplay between chromatin regulators and transcription factors. Here we show that activity of the Mi-2ß nucleosome-remodeling and histone-deacetylase (NuRD) complex was controlled by the Ikaros family of lymphoid lineage-determining proteins. Ikaros, an integral component of the NuRD complex in lymphocytes, tethered this complex to active genes encoding molecules involved in lymphoid differentiation. Loss of Ikaros DNA-binding activity caused a local increase in chromatin remodeling and histone deacetylation and suppression of lymphoid cell-specific gene expression. Without Ikaros, the NuRD complex also redistributed to transcriptionally poised genes that were not targets of Ikaros (encoding molecules involved in proliferation and metabolism), which induced their reactivation. Thus, release of NuRD from Ikaros regulation blocks lymphocyte maturation and mediates progression to a leukemic state by engaging functionally opposing epigenetic and genetic networks.


Subject(s)
Lymphocytes/enzymology , Mi-2 Nucleosome Remodeling and Deacetylase Complex/metabolism , Animals , Base Sequence , Cell Differentiation/genetics , Chromatin Assembly and Disassembly , Gene Expression Profiling , Gene Regulatory Networks , Ikaros Transcription Factor/genetics , Ikaros Transcription Factor/metabolism , Leukemia/genetics , Lymphocytes/immunology , Mice , Nucleotide Motifs , Protein Binding , Thymocytes/metabolism
8.
Immunity ; 33(5): 685-98, 2010 Nov 24.
Article in English | MEDLINE | ID: mdl-21093322

ABSTRACT

Loss of the transcription factor Ikaros is correlated with Notch receptor activation in T cell acute lymphoblastic leukemia (T-ALL). However, the mechanism remains unknown. We identified promoters in Notch1 that drove the expression of Notch1 proteins in the absence of a ligand. Ikaros bound to both canonical and alternative Notch1 promoters and its loss increased permissive chromatin, facilitating recruitment of transcription regulators. At early stages of leukemogenesis, increased basal expression from the canonical and 5'-alternative promoters initiated a feedback loop, augmenting Notch1 signaling. Ikaros also repressed intragenic promoters for ligand-independent Notch1 proteins that are cryptic in wild-type cells, poised in preleukemic cells, and active in leukemic cells. Only ligand-independent Notch1 isoforms were required for Ikaros-mediated leukemogenesis. Notch1 alternative-promoter usage was observed during T cell development and T-ALL progression. Thus, a network of epigenetic and transcriptional regulators controls conventional and unconventional Notch signaling during normal development and leukemogenesis.


Subject(s)
Gene Expression Regulation, Leukemic , Lymphocyte Activation/genetics , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics , Promoter Regions, Genetic , Receptor, Notch1/genetics , Signal Transduction/genetics , Animals , Epigenomics , Genetic Loci , Ikaros Transcription Factor/genetics , Ikaros Transcription Factor/metabolism , Mice , Receptor, Notch1/metabolism , T-Lymphocytes/metabolism
9.
Dev Cell ; 18(4): 633-42, 2010 Apr 20.
Article in English | MEDLINE | ID: mdl-20412777

ABSTRACT

The activity of keratinocytes in the hair follicle is regulated by signals from a specialized mesenchymal niche, the dermal papilla (DP). Here, mice expressing cre recombinase in the DP were developed to probe the interaction between follicular keratinocytes and the DP in vivo. Inactivation of the beta-catenin gene within DP of fully developed hair follicles results in dramatically reduced proliferation of the progenitors and their progeny that generate the hair shaft, and, subsequently, premature induction of the destructive phase of the hair cycle. It also prevents regeneration of the cycling follicle from stem cells. Gene expression analysis reveals that beta-catenin activity in the DP regulates signaling pathways, including FGF and IGF, that can mediate the DP's inductive effects. This study reveals a signaling loop that employs Wnt/beta-catenin signaling in both epithelial progenitor cells and their mesenchymal niche to govern and coordinate the interactions between these compartments to guide hair morphogenesis.


Subject(s)
Dermis/metabolism , Gene Expression Regulation, Developmental , Hair/embryology , Hair/physiology , beta Catenin/metabolism , Animals , Cell Proliferation , Gene Expression Profiling , Hair Follicle/embryology , Hair Follicle/physiology , Keratinocytes/cytology , Mesoderm/metabolism , Mice , Models, Biological , Morphogenesis , Signal Transduction , Stem Cells/cytology
10.
Epilepsia ; 51(12): 2461-5, 2010 Dec.
Article in English | MEDLINE | ID: mdl-21204807

ABSTRACT

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life-threatening severe cutaneous adverse reactions. Recently, strong associations of HLA-B*1502 with carbamazepine-induced SJS/TEN have been found in Han Chinese patients. These associations have been confirmed in several Asian populations, excluding Japanese. SJS patients carrying HLA-B*1508, HLA-B*1511, or HLA-B*1521, which are members of the HLA-B75 type along with HLA-B*1502, were detected in studies in India and Thailand. In the current study, we genotyped the HLA-B locus from 14 Japanese typical and atypical SJS/TEN patients in whom carbamazepine was considered to be involved in the onset of adverse reactions. Although there were no HLA-B*1502 carriers, four patients had HLA-B*1511. Our data suggest that HLA-B*1511, a member of HLA-B75, is a risk factor for carbamazepine-induced SJS/TEN in Japanese.


Subject(s)
Asian People/genetics , Carbamazepine/adverse effects , HLA-B Antigens/genetics , Stevens-Johnson Syndrome/genetics , Adolescent , Adult , Aged , Carbamazepine/therapeutic use , Child , Family , Female , Genotype , HLA-B15 Antigen , Humans , India , Male , Middle Aged , Pharmacogenetics , Risk Factors , Thailand
11.
Epilepsia ; 51(2): 297-300, 2010 Feb.
Article in English | MEDLINE | ID: mdl-19694795

ABSTRACT

Carbamazepine (CBZ) is frequently used for treating epilepsy, but this drug causes cutaneous adverse drug reactions (cADRs) that may range from mild to severe. It is reported recently that the human leukocyte antigen HLA-B*1502 is associated with Stevens-Johnson syndrome (SJS) induced by CBZ in Han Chinese. We examined HLA class I in 15 Japanese patients who fulfilled the diagnostic criteria for CBZ-induced cADRs (mild in 10 and severe = SJS in 5). HLA-B*1518, HLA-B*5901 and HLA-C*0704 alleles showed higher relative risks (above 10.0) for severe cADRs. The haplotype (HLA-A*2402-B*5901-C*0102) had high relative risk (16.09) for severe cADRs. In patients with severe cADRs, frequencies of HLA-A*1101, HLA-A*3303, HLA-B*1501, HLA-B*4403, HLA-B*5101, HLA-B*5201, HLA-C*0702, and HLA-C*1202 alleles are relatively lower than in the Japanese population. These data may suggest that HLA-B*5901 is one of the candidate markers for CBZ-induced SJS in Japanese.


Subject(s)
Asian People/genetics , Carbamazepine/adverse effects , Drug Eruptions/etiology , Epilepsy/drug therapy , Histocompatibility Antigens Class I/genetics , Stevens-Johnson Syndrome/chemically induced , Stevens-Johnson Syndrome/genetics , Adolescent , Adult , Alleles , Carbamazepine/therapeutic use , Child , Drug Eruptions/diagnosis , Drug Eruptions/epidemiology , Drug Hypersensitivity/genetics , Epilepsy/genetics , Female , Gene Frequency , Genetic Markers , HLA Antigens/genetics , HLA-B Antigens/genetics , HLA-B52 Antigen , Haplotypes/genetics , Humans , Infant , Male , Middle Aged , Pharmacogenetics , Risk Factors , Stevens-Johnson Syndrome/diagnosis
12.
Pharmacogenomics ; 9(11): 1617-22, 2008 Nov.
Article in English | MEDLINE | ID: mdl-19018717

ABSTRACT

INTRODUCTION: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but life-threatening severe cutaneous adverse reactions. Recently, strong associations of HLA-B*1502 and HLA-B*5801 with carbamazepine- and allopurinol-induced severe cutaneous adverse reactions were found in Han Chinese patients, respectively, but ethnic differences in the associations have been reported. The objective of this study is to clarify the involvement of HLA-B*1502 and HLA-B*5801 in Japanese SJS/TEN patients. METHODS: HLA-B genotyping was performed on 58 Japanese SJS/TEN patients between July 2006 and April 2008 from multicenters in Japan. RESULTS: There were no HLA-B*1502 carriers among 58 SJS/TEN patients. This patient group included seven carbamazepine-related and 11 aromatic anti-epileptic agent-related SJS/TEN patients. In addition, there were five HLA-B*5801 carriers, which included four allopurinol-related SJS/TEN patients. CONCLUSION: While HLA-B*1502 is unlikely to be associated with carbamazepine-related or aromatic anti-epileptic agent-related SJS/TEN, HLA-B*5801 was significantly associated with allopurinol-related SJS/TEN in Japanese.


Subject(s)
Allopurinol/adverse effects , Anticonvulsants/adverse effects , Asian People/genetics , HLA-B Antigens/genetics , Stevens-Johnson Syndrome/chemically induced , Stevens-Johnson Syndrome/etiology , Adolescent , Adult , Aged , Aged, 80 and over , Child , Female , Genotype , Humans , Japan , Male , Middle Aged , Severity of Illness Index , Stevens-Johnson Syndrome/diagnosis , Stevens-Johnson Syndrome/genetics , Young Adult
14.
Development ; 134(8): 1571-82, 2007 Apr.
Article in English | MEDLINE | ID: mdl-17360773

ABSTRACT

Using conditional gene targeting in mice, we show that the chromatin remodeler Mi-2beta is crucial for different aspects of skin development. Early (E10.5) depletion of Mi-2beta in the developing ventral epidermis results in the delayed reduction of its suprabasal layers in late embryogenesis and to the ultimate depletion of its basal layer. Later (E13.5) loss of Mi-2beta in the dorsal epidermis does not interfere with suprabasal layer differentiation or maintenance of the basal layer, but induction of hair follicles is blocked. After initiation of the follicle, some subsequent morphogenesis of the hair peg may proceed in the absence of Mi-2beta, but production of the progenitors that give rise to the inner layers of the hair follicle and hair shaft is impaired. These results suggest that the extended self-renewal capacity of epidermal precursors arises early during embryogenesis by a process that is critically dependent on Mi-2beta. Once this process is complete, Mi-2beta is apparently dispensable for the maintenance of established repopulating epidermal stem cells and for the differentiation of their progeny into interfollicular epidermis for the remainder of gestation. Mi-2beta is however essential for the reprogramming of basal cells to the follicular and, subsequently, hair matrix fates.


Subject(s)
Adenosine Triphosphatases/metabolism , Chromatin/metabolism , Epidermis/embryology , Hair Follicle/embryology , Stem Cells/cytology , Adenosine Triphosphatases/genetics , Animals , Cell Differentiation , DNA Helicases , Ectoderm/cytology , Ectoderm/metabolism , Epidermis/metabolism , Hair Follicle/metabolism , Mice , Mice, Transgenic
15.
Methods Mol Biol ; 289: 39-46, 2005.
Article in English | MEDLINE | ID: mdl-15502168

ABSTRACT

In this chapter, we describe an organ culture method that allows skin tissues isolated from 12.5- or 13.5-d postcoitus mouse embryos to develop in a manner histologically and temporally similar to the process in vivo. In this culture system, epidermal growth factor specifically and completely inhibited the hair follicle formation with marginal effects on interfollicular epidermis. Using an adenovirus vector, one can transduce a gene into the epidermal and dermal cell layers without appreciable toxicity.


Subject(s)
Cell Proliferation , Hair Follicle/cytology , Organ Culture Techniques/methods , Skin/cytology , Animals , Cell Culture Techniques , Embryo, Mammalian/cytology , Mice
16.
J Cell Biol ; 164(7): 979-84, 2004 Mar 29.
Article in English | MEDLINE | ID: mdl-15051732

ABSTRACT

Growth regulation of epithelial cells is of major concern because most human cancers arise from them. We demonstrated previously a novel signal pathway involving S100C/A11 for high Ca2+-induced growth inhibition of normal human keratinocytes (Sakaguchi, M., M. Miyazaki, M. Takaishi, Y. Sakaguchi, E. Makino, N. Kataoka, H. Yamada, M. Namba, and N.H. Huh. 2003. J. Cell Biol. 163:825-835). This paper addresses a question whether transforming growth factor beta (TGFbeta) shares the pathway with high Ca2+. On exposure of the cells to TGFbeta1, S100C/A11 was phosphorylated, bound to nucleolin, and transferred to the nucleus, resulting in induction of p21WAF1/CIP1 and p15INK4B through activation of Sp1. Protein kinase C alpha (PKCalpha) was shown to phosphorylate 10Thr of S100C/A11, which is a critical event for the signal transduction. The TGFbeta1-induced growth inhibition was almost completely mitigated when PKCalpha activity was blocked or when S100C/A11 was functionally sequestered. These results indicate that, in addition to the well-characterized Smad-mediated pathway, the PKCalpha-S100C/A11-mediated pathway is involved in and essential for the growth inhibition of normal human keratinocytes cells by TGFbeta1.


Subject(s)
Cell Division/drug effects , Keratinocytes/cytology , Protein Kinase C/metabolism , S100 Proteins/metabolism , Transforming Growth Factor beta/pharmacology , Animals , Cell Cycle Proteins/metabolism , Cell Line , Cell Nucleus/drug effects , Cell Nucleus/metabolism , Cell Nucleus/ultrastructure , Cyclin-Dependent Kinase Inhibitor p15 , Cyclin-Dependent Kinase Inhibitor p21 , Cyclins/metabolism , Epithelial Cells/cytology , Epithelial Cells/drug effects , Epithelial Cells/physiology , Humans , Keratinocytes/drug effects , Keratinocytes/physiology , Phosphoproteins/metabolism , Phosphorylation , Protein Kinase C-alpha , Protein Transport , RNA-Binding Proteins/metabolism , S100 Proteins/drug effects , Signal Transduction/drug effects , Signal Transduction/physiology , Tumor Suppressor Proteins/metabolism , Nucleolin
17.
J Biochem ; 132(6): 853-7, 2002 Dec.
Article in English | MEDLINE | ID: mdl-12473186

ABSTRACT

The eta isoform of protein kinase C (PKC eta) is classified into the Ca2+-independent novel PKC subfamily and assigned to human chromosome 14 (14q22-23) and mouse chromosome 12 (12C3-D2). It is highly expressed in epithelial tissues especially in squamous epithelia. PKC eta is unique in that it is specifically activated by cholesterol sulfate and sulfatide, sulfated metabolites of cholesterol and cerebroside, respectively. PKC eta overexpression induces G1 arrest and differentiation in keratinocytes. PKC eta-induced differentiation is accompanied by the transcriptional activation of transglutaminase I, a key enzyme in squamous differentiation, and involucrin, a precursor of cornified envelopes. In keratinocytes, PKC eta associates with the cyclin E/cdk2/p21 complex and inhibits the cdk2-kinase activity, leading to G1 arrest. Cholesterol sulfate inhibits the promotional phase of skin carcinogenesis. Moreover, PKC eta-knockout mice show a much higher sensitivity to carcinogenesis, suggesting that PKC eta is negatively involved in tumor promotion through stimulation of keratinocyte differentiation. In addition to epithelial cells, recent studies revealed that PKC eta acts as a key regulator in early B-cell development. Although the functions of PKC eta in other cell types are not yet fully elucidated, available evidence indicates that this particular isoform plays crucial roles in the signaling of cell differentiation in a cell-type-specific manner.


Subject(s)
Cell Differentiation/physiology , Isoenzymes/metabolism , Keratinocytes/metabolism , Protein Kinase C/metabolism , Animals , B-Lymphocytes/metabolism , Enzyme Activation , Humans , Isoenzymes/genetics , Protein Kinase C/genetics , Regulatory Sequences, Nucleic Acid , Tissue Distribution
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