Disease relevance of CDKN3

• These findings suggest that therapeutic intervention might be aimed at repression of KAP gene overexpression in human breast and prostate cancer [1].
• Choline availability modulates human neuroblastoma cell proliferation and alters the methylation of the promoter region of the cyclin-dependent kinase inhibitor 3 gene [2].
• Several aberrant KAP transcripts with characteristic deletion regions have been identified in hepatocellular carcinoma tissues [3].
• In this report, we demonstrated that multiple aberrant KAP transcripts were also present in a hepatoblastoma cell line (HepG2), albeit harboring a totally different set of deletions [3].
• Paradoxically, we find increased KAP mRNA expression in malignant astrocytomas, which correlates with increasing histologic grade and decreased patient survival [4].

Psychiatry related information on CDKN3

• PURPOSE: To (a) identify Chinese nurses' tobacco-related knowledge, attitude, and practice (KAP), including perception of competency in smoking-cessation interventions; (b) identify barriers and facilitators to smoking cessation interventions to patients; and (c) assess the learning needs and smoking status of nurses [5].
• A health education program for cancer risk reduction was conducted among 649 students out of 896 for whom Knowledge, Attitude and Practice (KAP) had been obtained at the initial study [6].

High impact information on CDKN3

• In HeLa cells, Cdi1 is expressed at the G1 to S transition, and the protein forms stable complexes with Cdk2 [7].
• These experiments identify Cdi1 as a novel type of protein phosphatase that forms complexes with cyclin-dependent kinases [7].
• Cdi1 bears weak sequence similarity to known tyrosine and dual specificity phosphatases [7].
• Overexpression of wild-type Cdi1 delays progression through the cell cycle in yeast and HeLa cells; delay is dependent on Cdi1 phosphatase activity [7].
• In vitro, Cdi1 removes phosphate from tyrosine residues in model substrates, but a mutant protein that bears a lesion in the putative active site cysteine does not [7].

Chemical compound and disease context of CDKN3

• Seventy-four adult patient with positive Vibrio cholerae 01 isolates were assigned to receive either ciprofloxacin in a single dose of 1 g (CIP1), or ciprofloxacin 500 mg b.i.d., for 1 day (CIP2), or doxycycline 100 mg b.i.d., for 3 days (D), or, for control, no antibiotics [8].

Biological context of CDKN3

• The kinase-activation segment interacts with the catalytic site of KAP almost entirely via the phosphate group of pThr-160 [9].
• Furthermore, lowering KAP expression led to inhibition of the transformed phenotype, with reduced anchorage-independent growth and tumorigenic potential in athymic nude mice [1].
• Blocking KAP expression by antisense KAP in a tetracycline-regulatable system results in a reduced population of S-phase cells and reduced Cdk2 kinase activity [1].
• We show that this interaction not only facilitates access of KAP to Thr160 and accelerates KAP kinetics, but also forces exclusion of cyclin A from the KAP.cdk2 complex [10].
• In Candida albicans, DDRT-PCR studies identified TIF-2, which may play a role in the upregulation of phospholipases, and the stress-related genes, CIP1 and CIP2 [11].

Anatomical context of CDKN3

• We have reported that KAP is bound and activated by a nuclear membrane protein, HTm4 [10].
• It binds to cyclin-dependent kinase-associated (CDK-associated) phosphatase-CDK2 (KAP-CDK2) complexes, and the three proteins demonstrate similar patterns of cellular expression in human lymphoid tissues [12].
• Cyclin-dependent kinase-associated phosphatase (KAP) was apparently translocated, as it was reduced (31% decrease) in cytosolic fractions but elevated (100% increase) in particulate fractions of ALS spinal cord tissue [13].
• Hair follicle in situ hybridization data for single members of five different KAP multigene families all showed localization of the respective mRNAs to the upper cortex of the hair shaft [14].
• Targeting of alpha-kinase-anchoring protein (alpha KAP) to sarcoplasmic reticulum and nuclei of skeletal muscle [15].

Associations of CDKN3 with chemical compounds

• Mean liquid stool output volume did not show any statistically significant difference among CIP1, CIP2 and doxycycline groups The mean duration of diarrhoea in CIP1 group, on the other hand, was significantly lower than that from the D group (p = 0.004), and the control group (p < 0.001) [8].
• Comparisons of promoter regions of IF genes and KAP genes, including a recently characterized gene for a glycine/tyrosine-rich protein, have revealed putative hair-specific motifs in addition to known elements that regulate gene expression [16].
• Our results show that alpha KAP is largely localized at the free SR and thus near the Ca(2+) pump, a protein that can be modulated by CaM kinase II phosphorylation [15].

Physical interactions of CDKN3

• We describe the structure of phospho-CDK2 in complex with kinase-associated phosphatase, and discuss the substrate recognition promoted by interactions that are remote from the catalytic site [17].

Enzymatic interactions of CDKN3

• KAP was unable to dephosphorylate Tyr15 and only dephosphorylated Thr160 in native monomeric Cdk2 [18].

Regulatory relationships of CDKN3

• Thus, KAP regulates both cdc2-dependent migration and Cdk2-dependent proliferation, and its loss due to aberrant splicing increases malignancy in human gliomas [4].

Other interactions of CDKN3

• Abolishment of the interaction between cyclin-dependent kinase 2 and Cdk-associated protein phosphatase by a truncated KAP mutant [3].
• Here, we present in vitro data showing the direct interaction between the HTm4 C terminus and KAP Tyr141 [10].
• Experiments confirm that CDK7 is not a substrate for kinase-associated phosphatase [19].
• Since KAP is not significantly similar to known phosphatases beyond the catalytic core motif, it represents an additional class of dual specificity phosphatase [20].
• For cells to exit mitosis, the CDKs must be completely inactivated, firstly by the ubiquintin-mediated destruction of the cyclins, followed by dephosphorylation of phospho-Thr160 (in CDK2) catalysed by the kinase-associated phosphatase and protein phosphatase 2C [17].

Analytical, diagnostic and therapeutic context of CDKN3

• We have identified the KAP gene as an overexpressed gene in breast and prostate cancer by using a phosphatase domain-specific differential-display PCR strategy [1].
• By performing yeast two-hybrid and co-immunoprecipitation experiments, a KAP-Cdk2 interaction domain located in the amino acid 1-34 region was identified [3].
• To investigate whether mutations of this enzyme occur in hepatocellular carcinoma (HCC), KAP mRNA was analyzed by reverse transcription-PCR (RT-PCR), followed by cloning and sequencing [21].
• Through a combination of proteomic screening and site-directed mutagenesis approaches, we have identified lysines 554, 779, and 804 as the major sumoylation sites in KAP1 [22].
• Bacteriologic clearance at the fourth day of treatment were 95.2% for CIP1, 89.5% for CIP2, 90.5% for D group and 15.4% for the control group [8].

References