Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The initiation of mitosis requires the activation of M-phase promoting factor (MPF). MPF activation and its subcellular localization are dependent on the phosphorylation state of its components, cdc2 and cyclin B1. In a two-hybrid screen using a bait protein to mimic phosphorylated cyclin B1, we identified a novel interaction between cyclin B1 and patched1 (ptc1), a tumor suppressor associated with basal cell carcinoma (BCC). Ptc1 interacted specifically with constitutively phosphorylated cyclin B1 derivatives and was able to alter their normal subcellular localization. Furthermore, addition of the ptc1 ligand, sonic hedgehog (shh), disrupts this interaction and allows cyclin B1 to localize to the nucleus. Expression of ptc1 in 293T cells was inhibitory to cell proliferation; this inhibition could be relieved by coexpression of a cyclin B1 derivative that constitutively localizes to the nucleus and that could not interact with ptc1 due to phosphorylation-site mutations to ALA: In addition, we demonstrate that endogenous ptc1 and endogenous cyclin B1 interact in vivo. The findings reported here demonstrate that ptc1 participates in determining the subcellular localization of cyclin B1 and suggest a link between the tumor suppressor activity of ptc1 and the regulation of cell division. Thus, we propose that ptc1 participates in a G(2)/M checkpoint by regulating the localization of MPF.
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PMID:Patched1 interacts with cyclin B1 to regulate cell cycle progression. 1133 87

Mutations in the transmembrane receptor patched1 (ptc1) are responsible for the majority of basal cell carcinoma (BCC) cases. Many of these mutations, including ptc1-Q688X, result in premature truncation of the ptc1 protein. ptc1-Q688X has been identified in patients with both BCC and nevoid basal cell carcinoma syndrome, an inheritable disorder causing a predisposition to cancer susceptibility. Here we describe a mechanism by which ptc1-Q688X causes constitutive cellular signaling. Cells expressing ptc1-Q688X demonstrate an increase in cell cycle progression and induce cell transformation. The ptc1-Q688X mutant enhances Gli1 activity, a downstream reporter of sonic hedgehog (shh)-ptc1 signaling, independent of shh stimulation. In contrast to wild-type ptc1, ptc1-Q688X fails to associate with endogenous cyclin B1. Expression of nuclear-targeted cyclin B1 derivatives promotes Gli1-dependent transcription, which correlates temporally with cyclin B1-cdk1 kinase activity. Coexpression of wild-type ptc1 with a nuclear-targeted cyclin B1 derivative, mutated to mimic constitutive phosphorylation, dramatically decreases Gli1 activity. In addition, the coexpression of this constitutively nuclear cyclin B1 derivative with ptc1-Q688X substantially enhances foci formation. These studies therefore describe a molecular mechanism for the aberrant activity of ptc1-Q688X that includes the premature activation of the transcription factor Gli1.
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PMID:Constitutive activation of the shh-ptc1 pathway by a patched1 mutation identified in BCC. 1559 20

Hyperproliferative epidermal disorders range from benign hyperplasias such as psoriasis to basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), the two most common cancers in the US. While they all arise from the epidermis, these diseases differ dramatically in biological behavior and their underlying gene expression patterns have not been compared. We thus examined mRNA transcript levels in these disorders to identify and further characterize differentially expressed genes. Transcript expression patterns distinguish these disorders and identify EGR1, among other genes, whose epidermal expression is decreased in BCC and SCC but is elevated in psoriasis. Egr-1 inhibits growth of benign and malignant epidermal cells in vitro and appears to suppress both Cdc25A expression and Cdk2 dephosphorylation. These data indicate that gene expression profiling can differentiate epidermal hyperproliferative diseases and suggest that Egr-1 may play a role in preventing uncontrolled epidermal growth.
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PMID:Evidence of EGR1 as a differentially expressed gene among proliferative skin diseases. 1892 31

Lesions originating from different types of skin cells differ significantly with respect to their pathologic importance. The aim of this work was to examine as to what extent the differences in the origin are reflected in expression levels of CDK-2 and to investigate whether CDK-2 expression might be considered as potential marker useful for diagnostics and assessment of invasiveness of human nonmelanocytic lesions. We conducted comparative immunohistochemical studies of expression of cyclin-dependent kinase 2 (CDK-2) in 16 benign epithelial skin lesions, 11 precancerous lesions, 19 cases of basal cell carcinoma (first such study), 14 squamous cell carcinomas (SCCs), and 7 fibromas. Development of benign epithelial skin lesions was not associated with considerable increase of the CDK-2 expression. Increase of the CDK-2 level was observed in precancerous lesions, and the expression was strongest in SCCs. The level of CDK-2 may be related to invasiveness of skin cancers, as squamous cell carcinomas expressed the enzyme significantly stronger than basal cell carcinomas. Higher percentage fraction of CDK-2 positive cells observed in SCC compared with precancerous lesions may be useful for histopathologic diagnostics of this cancer. Moreover, strong immunohistochemical CDK-2 staining of the cancer cells present deep in dermis may facilitate their detection in histopathologic examinations.
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PMID:Cyclin-dependent kinase 2 (CDK-2) expression in nonmelanocytic human cutaneous lesions. 2021 5