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)

Fanconi anemia (FA) is an autosomal recessive disorder characterized by developmental defects, bone marrow failure, and cancer susceptibility. Cells derived from FA patients are sensitive to crosslinking agents and have a prolonged G2 phase, suggesting a cell cycle abnormality. Although transfection of type-C FA cells with the FAC cDNA corrects these cellular abnormalities, the molecular function of the FAC polypeptide remains unknown. In the current study we show that expression of the FAC polypeptide is regulated during cell cycle progression. In synchronized HeLa cells, FAC protein expression increased during S phase, was maximal at the G2/M transition, and declined during M phase. In addition, the FAC protein coimmunoprecipitated with the cyclin-dependent kinase, cdc2. We next tested various mutant forms of the FAC polypeptide for binding to cdc2. A patient-derived mutant FAC polypeptide, containing a point mutation at L554P, failed to bind to cdc2. The FAC/cdc2 binding interaction therefore correlated with the functional activity of the FAC protein. Moreover, binding of FAC to cdc2 was mediated by the carboxyl-terminal 50 amino acids of FAC in a region of the protein required for FAC function. Taken together, our results suggest that the binding of FAC and cdc2 is required for normal G2/M progression in mammalian cells. Absence of a functional interaction between FAC and cdc2 in FA cells may underlie the cell cycle abnormality and clinical abnormalities of FA.
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PMID:The Fanconi anemia polypeptide, FAC, binds to the cyclin-dependent kinase, cdc2. 924 35

Fanconi anemia (FA) is an autosomal recessive disease marked by congenital defects, bone marrow failure, and cancer susceptibility. FA cells exhibit a characteristic hypersensitivity to DNA crosslinking agents such as mitomycin C. The molecular mechanism for the disease remains elusive, but at least 6 FA proteins are known to be part of what is termed the FA core complex. We used affinity pulldown of FLAG-FANCA to pull down the FA complex from whole-cell extracts. Mass spectroscopy detected previously reported FA-binding proteins, including FANCA, FANCC, FANCG, cdc2, and GRP94, thus validating the approach. We further describe a method of purification of the FA core complex in an effort to find novel complex components and biochemical activity to define the function of the complex. By using conventional chromatographic fractionation of subcellular preparations, we report: (i) the FA core complex exists in a cytoplasmic form at 500-600 kDa; (ii) a larger, 750-kDa cytoplasmic form is seen only at mitosis; (iii) a nuclear form achieves a size of 2 megaDaltons; and (iv) a distinct 1-megaDalton FA core complex exists bound to chromatin that contains phosphorylated FANCA after undergoing DNA damage. We are continuing our analysis using mass spectroscopy in an effort to characterize novel binding proteins. These data will help define the biochemical role of the FA core complex in normal cell physiology as well as in the development of the FA disease state.
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PMID:The Fanconi anemia core complex forms four complexes of different sizes in different subcellular compartments. 1508 18

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