Elevated levels of protein kinase CK2 (formerly casein kinase 2 or II) have long been associated with increased cell growth and proliferation both in normal and cancer cells. The ability of CK2 to also act as a potent suppressor of apoptosis offers an important link to its involvement in cancer since deregulation of both cell proliferation and apoptosis are among the key features of cancer cell biology. Dysregulated CK2 may impact both of these processes in cancer cells. All cancers that have been examined show increased CK2 expression, which may also relate to prognosis. The extensive involvement of CK2 in cancer derives from its impact on diverse molecular pathways controlling cell proliferation and cell death. Downregulation of CK2 by various approaches results in induction of apoptosis in cultured cell and xenograft cancer models suggesting its potential as a therapeutic target.
Protein kinase CK2, a protein serine/threonine kinase, plays a global role in activities related to cell growth, cell death and cell survival. CK2 has a large number of potential substrates localized in diverse locations in the cell including, e.g., NF-κB as an important downstream target of the kinase. In addition to its involvement in cell growth and proliferation it is also a potent suppressor of apoptosis, raising its key importance in cancer cell phenotype. CK2 interacts with diverse pathways which illustrates the breadth of its impact on the cellular machinery of both cell growth and cell death giving it the status of a "master regulator" in the cell. With respect to cancer, CK2 has been found to be dysregulated in all cancers examined demonstrating increased protein expression levels and nuclear localization in cancer cells compared with their normal counterparts. We originally proposed CK2 as a potentially important target for cancer therapy. Given the ubiquitous and essential for cell survival nature of the kinase, an important consideration would be to target it specifically in cancer cells while sparing normal cells. Towards that end, our design of a tenascin based sub-50 nm (i.e., less than 50 nm size) nanocapsule in which an anti-CK2 therapeutic agent can be packaged is highly promising because this formulation can specifically deliver the cargo intracellularly to the cancer cells in vivo. Thus, appropriate strategies to target CK2 especially by molecular approaches may lead to a highly feasible and effective approach to eradication of a given cancer.
Although it has been reported that cyclin L1␣ and L2␣ proteins interact with CDK11 p110 , the nature of the cyclin L transcripts, the formation of complexes between the five cyclin L and the three CDK11 protein isoforms, and the influence of these complexes on splicing have not been thoroughly investigated. Here we report that cyclin L1 and L2 genes generate 14 mRNA variants encoding six cyclin L proteins, one of which has not been described previously. Using cyclin L gene-specific antibodies, we demonstrate expression of multiple endogenous cyclin L proteins in human cell lines and mouse tissues. Moreover, we characterize interactions between CDK11 p110 , mitosis-specific CDK11 p58 , and apoptosis-specific CDK11 p46 with both cyclin L␣ and - proteins and the co-elution of these proteins following size exclusion chromatography. We further establish that CDK11 p110 and associated cyclin L␣/ proteins localize to splicing factor compartments and nucleoplasm and interact with serine/arginine-rich proteins. Importantly, we also determine the effect of CDK11-cyclin L complexes on pre-mRNA splicing. Preincubation of nuclear extracts with purified cyclin L␣ and - isoforms depletes the extract of in vitro splicing activity. Ectopic expression of cyclin L1␣, L1, L2␣, or L2 or active CDK11 p110 individually enhances intracellular intron splicing activity, whereas expression of CDK11 p58/p46 or kinase-dead CDK11 p110 represses splicing activity. Finally, we demonstrate that expression of cyclins L␣ and - and CDK11 p110 strongly and differentially affects alternative splicing in vivo. Together, these data establish that CDK11 p110 interacts physically and functionally with cyclin L␣ and - isoforms and SR proteins to regulate splicing.It has become apparent over the past decade that several cyclin-dependent kinases (CDKs) 4 and their cyclin regulatory partners participate in regulating mRNA production (1). Thus far, CDK7, CDK8, and CDK9 functions are ascribed to transcriptional initiation and elongation, and CDK12 (CrkRS) and CDK13 (CDC2L5) functions are related to pre-mRNA splicing (2-4). Interestingly, CDK11 p110 plays roles in both transcription and splicing, suggesting that this CDK may link the two processes (5, 6). In addition, the CDK11 p110 partner proteins cyclins L1 and L2 also influence splicing (7,8). Two distinct genes, Cdc2L1 and Cdc2L2 (acronym for Cell division control 2 Like), encode the human p110 and p58 PITSLRE protein kinases (9 -12). These kinases were renamed CDK11 p110 and CDK11 p58 when cyclins L1 and L2 were identified as regulatory subunits of CDK11 p110 (13). Expression of the CDK11 p110 isoforms is ubiquitous and constant throughout the cell cycle (11). In contrast, CDK11 p58 is expressed and functions specifically in G 2 /M via an internal ribosome entry site (IRES) located within the CDK11 p110 mRNA (14 -17). During apoptosis, a third isoform, CDK11 p46 , is generated by caspase-dependent cleavage of CDK11 p110 and CDK11 p58 , leaving the catalytic domain intact (18,19).A role for CDK11 p...
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