Disease relevance of CDK2AP1

• Here, we have analyzed expression and prognostic relevance of the cdk2-associated cyclins in non-small cell lung cancer (NSCLC) [1].
• Cyclin E is the only cyclin-dependent kinase 2-associated cyclin that predicts metastasis and survival in early stage non-small cell lung cancer [1].
• CDK2 associated with RNAPII and was found in elongation complexes assembled on HIV-1 long-terminal repeat template [2].
• Differential expression of DOC-1 in microsatellite-unstable human colorectal cancer [3].
• CONCLUSIONS: These results allow us to conclude that reduction of p12DOC-1 protein expression is a frequent event in oral cancers [4].

High impact information on CDK2AP1

• Expression of p16(INK4a) inhibited G(1)/S transition induced in MCF-7 cells by 17-beta-estradiol (E(2)) with associated inhibition of both Cdk4- and Cdk2-associated kinase activities [5].
• Ectopic expression of p12(DOC-1) resulted in decreased cellular CDK2 and reduced CDK2-associated kinase activities and was accompanied by a shift in the cell cycle positions of p12(DOC-1) transfectants ( upward arrow G(1) and downward arrow S) [6].
• Synchronization of tumor cells by lovastatin, which arrests cells in G1, resulted in increased levels of p21 and p27 with a concomitant decrease in cyclin-dependent kinase 2-associated kinase activity [7].
• However, cells became arrested prior to entry into S phase in a manner that paralleled the repression of cdk2-associated kinase activity [8].
• The CDK2-associated cyclin A1 is essential for spermatogenesis and contributes to leukemogenesis [9].

Biological context of CDK2AP1

• Therefore, identification of other p12(DOC-1/CDK2AP1) interacting proteins might clarify its role in the cell cycle regulation and carcinogenesis [10].
• Using human p12(DOC-1/CDK2AP1) as a bait in a liver cDNA library screening, cDNA clones identical to human DOC-1R transcript were identified [10].
• We have identified a novel gene from chromosome 11q13, which encodes a protein of 126 amino acids sharing an overall 57% identity with the p12(DOC-1) protein encoded by the DOC-1 gene, the human homolog of hamster putative tumor suppressor doc-1 (deleted in oral cancer-1) [11].
• We also observed alterations in the biologic behavior of p12(DOC-1)-deficient cell lines, with increased S phase and decreased apoptosis compared to microsatellite-stable (DOC-1+) cell lines [3].
• DOC-1 expression correlated with microsatellite status, with significantly decreased expression in microsatellite-unstable cell lines and constitutive expression in microsatellite-stable cell lines [3].

Anatomical context of CDK2AP1

• Survival analysis showed significant correlation of low p12DOC-1 expression with the risk of cervical lymph node metastasis (P = 0.001) and patients' 10-year survival status (P = 0.0214) [4].
• RESULTS: Our results showed that strong p12DOC-1 staining was uniformly seen in normal oral mucosa. p12DOC-1 staining was reduced or absent in 81 cases (63.8%) of oral squamous cell carcinomas [4].
• The cyclin A transgene products were localized in the nuclei of mammary epithelial cells, and the transgenic mammary glands had an increase in cyclin A- and cdk2-associated H1 kinase activity [12].
• Transfection of doc-1 into malignant oral keratinocytes leads to increased cell loss [13].

Associations of CDK2AP1 with chemical compounds

• Lyn was associated with Cdk2; Cdk2-associated Lyn was heavily phosphorylated on serine and threonine residues both in vitro and in situ during S-phase [14].
• CONCLUSION: Doxazosin induces the apoptosis of cardiomyocytes via the ER pathway, with increased production of C/EBP beta, GADD153 and DOC-1 [15].
• A trypan blue exclusion assay was performed to examine cell death in the parental or wild-type HCPC-1 keratinocytes, HCPC-1 transfected with the parental pcDNA3 vector, and the doc-1 transfected HCPC-1 cells [13].

Physical interactions of CDK2AP1

• The loss of stable p21(WAF1)/cyclin E/CDK2 complexes coincided with an increase in CDK2-associated kinase activity and cyclin E levels [16].
• These findings suggest that the overexpression of cyclin E reverses the p27(Kip1) mediated G1 growth arrest by binding the inhibitor restoring the cdk2 associated kinase activity necessary for the G1/S transition [17].

Regulatory relationships of CDK2AP1

• PURPOSE: p12DOC-1 is a growth suppressor that negatively regulates cyclin-dependent kinase 2 (CDK2) activities [4].

Other interactions of CDK2AP1

• Thus CGP 41251 inhibits CDC2- and CDK2-associated kinase activities both in vivo and in vitro [18].
• RA-induced cell cycle arrest is also associated with induction of p27Kip1 expression, inhibition of cdk2-associated kinase activity and alteration of the phosphorylation state of the pRB-family proteins [19].
• Ectopic overexpression of p21cip1/waf1 was associated with inhibition of CDK2-associated kinase activity, indicating the functionality of the introduced p21cip1/waf1 gene [20].
• Interestingly, when wild-type MMR protein - MLH1 - was induced in an in vitro human recombinant system, the del T poly (T)8 mutation was reversed and CDK2-AP1 expression increased [21].
• There were 27 "3-set" genotypes, 24 multilocus sequence types (STs), and 35 unique combinations (or strains), of which the 4 most common, msst III-2 (ST-17), msst III-1 (ST-19), Ia-1 (ST-23), and V-1 (ST-1), accounted for more than 60% of isolates [22].

Analytical, diagnostic and therapeutic context of CDK2AP1

• The purpose of this study is to correlate in vivo the expression of p12DOC-1 in oral cancer tissues by immunohistochemistry with clinical and pathological parameters [4].
• We mapped DOC1 to chromosome band 12q24.31 by fluorescence in situ hybridization [23].
• TUNEL assays (P < .05) and annexin V/PI FACS analysis (P < .05) also showed early cytochemical changes in the doc-HCPC-1 transfectants, confirming that ectopic expression of doc-1 induces apoptosis [13].

References