Disease relevance of CDC2L2

• Western blot analysis revealed decreased level of PITSLRE protein expression in several cell lines, as well as in four surgical malignant melanoma specimens relative to normal melanocytes [1].
• Alterations in the PITSLRE protein kinase gene complex on chromosome 1p36 in childhood neuroblastoma [2].
• Interestingly, phosphorylation of eIF-2alpha has a permissive effect on the efficiency of both the PITSLRE IRES and the ornithine decarboxylase IRES, two cell cycle-dependent IRESs, in mediating internal initiation of translation, whereas this was not observed with the viral EMCV (encephalomyocarditis virus) and HRV (human rhinovirus) IRESs [3].

High impact information on CDC2L2

• Our data suggest the existence of an IRES-dependent cascade in mitosis comprising hnRNP C1/C2 proteins that stimulate Unr expression, and Unr, in turn, contributes to PITSLRE IRES activity [4].
• For example, the Unr protein contributes to translation mediated by several viral and cellular internal ribosome entry sites (IRESs), including the PITSLRE IRES, which is activated at mitosis [4].
• PITSLRE protein kinase activity is associated with apoptosis [5].
• To test this hypothesis, we examined levels of PITSLRE mRNA, steady-state protein, and enzyme activity in human T cells undergoing apoptosis after activation with the anti-Fas monoclonal antibody (MAb) [5].
• Minimal ectopic expression of a 58-kDa protein kinase (PITSLRE beta 1), distantly related to members of the cdc2 gene family, induces telophase delay, abnormal chromosome segregation, and decreased growth rates in Chinese hamster ovary cells [5].

Biological context of CDC2L2

• The two genes encoding the PITSLRE protein kinase isoforms, CDC2L1 and CDC2L2, are localized to human chromosome band 1p36 [1].
• In this paper we report that tumor necrosis factor (TNF)-mediated apoptosis is associated with a CrmA- and Bcl-2-inhibitable cleavage of PITSLRE kinases, indicating a role for CASPs [6].
• Effect of p58GTA on beta-1,4-galactosyltransferase 1 activity and cell-cycle in human hepatocarcinoma cells [7].
• Abnormalities in the p34cdc2-related PITSLRE protein kinase gene complex (CDC2L) on chromosome band 1p36 in melanoma [1].
• By flow cytometry analysis, it was found that the p58GTA/7721 cells were G2/M phase arrested, compared with the pcDNA3/7721 cells [7].

Anatomical context of CDC2L2

• TNF-induced proteolysis of PITSLRE kinases was still observed in fibroblasts from CASP-1(0/0) mice [6].
• Transient expression of the p58GTA protein kinase, which belongs to the p34cdc2-related supergene family, could enhance beta1,4-GT 1 total activity in COS cells [7].
• Here we show that multiple caspase-like activities are involved in the processing of the PITSLRE p110 isoforms during Fas-induced apoptosis in Jurkat T-cells [8].
• Finally, we demonstrate that the PITSLRE p110 protein is rapidly phosphorylated during Fas-induced apoptosis in Jurkat cells and that phosphorylation of an amino-terminal portion of the protein may enhance caspase cleavage in this region [8].
• The PITSLRE/CDK11p58 protein kinase promotes centrosome maturation and bipolar spindle formation [9].

Associations of CDC2L2 with chemical compounds

• These results suggest that the p58GTA stable transfection into human hepatocarcinoma cells could enhance the two beta1,4-GT1 subcellular pool activities independently and change its cell-cycle without modifying the beta-1,4-linked galactose residues on most membrane proteins [7].
• In this study, the p58GTA interaction with beta1,4-GT 1 was confirmed using an in vitro assay with the TNT Coupled Reticulocyte Lysate System. An expression vector containing p58GTA was stably transfected into 7721 cells, a human hepatocarcinoma cell line, expression was confirmed by Northern and Western blot analyses [7].
• Progressive deletion analysis showed that both a purine-rich sequence and a Unr (upstream of N-ras) consensus binding site are essential for PITSLRE IRES activity [3].
• These findings suggest that (i) PITSLRE kinase(s) may lie within apoptotic signaling pathway(s), (ii) serine protease activation may be an early event in Fas-activated apoptosis of human T cells, and (iii) some PITSLRE kinase isoforms may be targets of apoptotic proteases [5].
• Furthermore, 2-aminopurine inhibits PITSLRE beta 1 protein kinase activity in vivo, but does not effect p34cdc2 protein kinase activity in a similar manner [10].

Physical interactions of CDC2L2

• These data indicate that the PITSLRE p110 isoforms interact with RNPS1 in vivo, and that these proteins may in turn influence some aspect of transcriptional and/or splicing regulation [11].
• We demonstrate that PITSLRE p110 protein kinases co-immunoprecipitate and/or co-purify with these elongation factors as well as with RNA polymerase II [12].

Other interactions of CDC2L2

• Here we demonstrate that the 110 kDa PITSLRE isoforms (p110) are localized to both the nucleoplasm and nuclear speckles, and that these isoforms specifically interact in vitro and in vivo with the RNA-binding protein RNPS1 [11].
• Thus, the decreased PITSLRE protein expression appears to result from deletion of the CDC2L alleles and possibly by mutations within the 5' promoter region [1].
• CDK11p110 (cyclin-dependent kinase 11p110, formerly known as PITSLRE) is a member of the CDK superfamily [13].
• The C-terminal kinase domain of the p34cdc2-related PITSLRE protein kinase (p110C) associates with p21-activated kinase 1 and inhibits its activity during anoikis [14].
• The caspase-processed cyclin-dependent kinase 11 (formerly known as PITSLRE) is implicated in apoptotic signaling [15].

Analytical, diagnostic and therapeutic context of CDC2L2

• Molecular cloning and expression of alternatively spliced PITSLRE protein kinase isoforms [16].
• Finally, fluorescence confocal microscopy revealed a nuclear localization of PITSLRE proteins in normal melanocytes and A375 cells but a cytoplasmic localization in UACC 1227 cells [17].
• Approximately 6-12 hours after treatment with okadaic acid, mRNA levels of c-myc, p34cdc2, and p58GTA, two cell cycle regulated protein kinases, decrease [18].
• Like humans, the PITSLRE PK genes in chickens must be closely linked, based on fluorescent in situ hybridization (FISH) localization of these genes to a single chicken microchromosome [19].

References