Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

CDK11

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_546

Synonyms

Historical Background

The CDK11A and CDK11B kinases (cyclin-dependent kinase 11A and B), formerly known as PITSLRE protein kinases, are serine/threonine protein kinases that belong to p34CDC2-related protein kinase superfamily. p34CDC2-related kinases play essential roles in many aspects of the cellular processes, especially cell cycle control and the regulation of transcription. There are two CDK11 genes in humans (CDK11A and CDK11B formerly known as CDC2L2 and CDC2L1), and one CDK11 gene in mouse (Cdk11, previously known as cdc2l) (Malumbres et al. 2009). CDK11 genes are evolutionarily conserved. CDK11 homologs are found in human, mouse, rat, frog, cattle, fruit fly, yeast, and even in protozoa amoeba (Trembley et al. 2004; Goldberg et al. 2006). The almost identical human CDK11A and CDK11B genes are tandemly located within ∼140 kb on chromosome 1p36.33. Each gene contains 20 exons and 19 introns and the full-length CDK11Ap110 and CDK11Bp110 proteins differ by only 16 amino acids (Gururajan et al. 1998; Lahti et al. 1994; Trembley et al. 2004). All data to date suggest that these two genes are functionally equivalent; therefore, to simplify the nomenclature, we will use the term “CDK11” to represent the human genes and proteins as well as the single mouse gene and protein in the following text.

CDK11 mRNA and protein are expressed in all cell types examined to date, although the mRNA and proteins are most abundant in testes, bone marrow, spleen, brain, lymph nodes, thymus, and hematopoietic cell lines (Xiang et al. 1994). The three major CDK11 isoforms are CDK11p110, CDK11p58, and CDK11p46 (Fig. 1). There are many human transcript variants encoding the most abundant CDK11 isoform, CDK11p110. These transcripts are generated by alternate promoter usage and alternative splicing of exons 1–11 which are located upstream of the Ser/Thr protein kinase domain of the CDK11 genes. CDK11p110 is expressed throughout the cell cycle. In contrast, CDK11p58 is specifically expressed during G2/M (Gap 2 and mitosis) phase of the cell cycle. This protein is generated via an IRES (internal ribosome entry site) located within the coding region of the CDK11 full-length transcript (Cornelis et al. 2000; Wilker et al. 2007). Finally, CDK11p46 is produced by caspase-mediated cleavage of both CDK11p110 and CDK11p58 during apoptosis (Lahti et al. 1995; Beyaert et al. 1997; Tang et al. 1998). Like other CDKs, CDK11 protein kinases are associated with and regulated by the cyclin partners, cyclin L1 and L2 (Dickinson et al. 2002; Loyer et al. 2008).
CDK11, Fig. 1

The schematic diagram of the human CDK11 gene, transcript, and the major protein isoforms. The human CDK11A and CDK11B genes are located on chromosome 1p36.33. The exons are represented by the green bars. Several known functioning motifs are indicated on the full-length CDK11p110 diagram, and the relative location of the internal ribosomal entry site (IRES) element facilitating the mitotic expression of CDK11p58 is indicated on the transcript. The caspase cleavage sites used for generating apoptotic CDK11p46 are also indicated by arrows on the full-length protein Additional CDK11 isoforms are generated by alternative splicing of exons 1–11 of the pre-mRNA

CDK11 is an essential gene. Genetic deletion of the Cdk11 gene in mouse leads to early embryonic lethality at E3.5 (embryonic day 3.5), while the heterozygous mice (CDK11+/− mice) appear to develop normally (Li et al. 2004). Likewise, decreasing CDK11 expression using siRNA leads to mitosis abnormalities, apoptosis, and cell death (Hu et al. 2007; Petretti et al. 2006). Interestingly, heterozygous deletion or translocations of the human CDK11 genes are frequently observed, implying its role in tumorigenesis (Trembley et al. 2004). In addition to potential roles in tumorigenesis and mitosis, data published to date have shown that CDK11 is involved in transcription, RNA processing, neuronal signaling, apoptosis, and cell cycle regulation.

CDK11 and Transcription

The first clue that CDK11 might be involved in transcriptional regulation came from yeast two-hybrid studies using CDK11p110 as a bait protein. The RNA polymerase II transcription elongation factor ELL2 was identified as a CDK11p110 interacting protein in these studies (Trembley et al. 2002). Characterization of purified CDK11 complexes from Hela nuclear extracts revealed that the largest subunit of RNA polymerase II (RNAP II), the SSRP1 (structure-specific recognition protein 1), and SPT16 (chromatin-specific transcription elongation factor 140 kDa subunit) subunits of the transcription elongation factor FACT (facilitates chromatin transcription, a histone chaperone) and Casein kinase II (CKII) and ELL2, all proteins involved in transcription, are present in CDK11p110 complexes. Furthermore, coimmunoprecipitation analyses indicated that CDK11p110 associates with the TFIIF (transcription initiation factor IIF), TFIIS (transcription elongation factor IIS), and both hypo- and hyperphosphorylated forms of the largest subunit of RNAP II. Importantly, addition of CDK11 antibody, which binds to the carboxyl terminal domain of CDK11 and presumably disrupts interactions between CDK11 and transcriptional complex proteins, substantially reduced the production of RNA transcript in an in vitro transcription assay (Trembley et al. 2002, 2003).

CDK1, CDK7, CDK8, and CDK9 are also involved as transcription regulators and phosphorylate the carboxyl-terminal domain (CTD) of RNAP II complexes to positively or negatively regulate transcription (reviewed in Hirose and Ohkuma 2007). In contrast, CDK11p110 does not directly phosphorylate the RNAPII CTD; however, CDK11p110 interacts with casein kinase II (CKII) which phosphorylates both CDK11 and the RNAP II CTD (Trembley et al. 2002, 2003, 2004). Recent report also showed that CDK11 promotes HIV mRNA expression and stability through its association with the transcription/export complex (Pak et al. 2015). Despite data clearly indicating that CDK11p110 interacts with transcriptional proteins and is required for high level in vitro transcription, the exact role of CDK11p110 in transcription in vivo and the biological substrates of the kinase remain undetermined.

CDK11 and RNA Processing

The role of CDK11p110 is consistent with the fact that CDK11p110 has several putative nuclear localization signal sequences. Indirect immunofluorescence analysis of CDK11 localization revealed that a portion of the cellular CDK11p110 is diffusely localized in the nucleoplasm, while the majority of the protein is found in nuclear speckles. These nuclear speckles also contain general splicing factors suggesting that CDK11p110 may also play a role in splicing. Consistent with this hypothesis, the splicing factors RNPS1 and 9G8 were identified as CDK11p110 interacting proteins by yeast two-hybrid analyses and 9G8 is phosphorylated by CDK11p110 (Loyer et al. 1998; Hu et al. 2003). Additionally, the CDK11 regulatory proteins, cyclin L1 and L2, have roles in RNA splicing (Loyer et al. 1998, 2008; Dickinson et al. 2002; Hu et al. 2003).

Further evidence for the role of CDK11p110 in splicing was demonstrated both in vitro and in vivo. Immunodepletion of CDK11p110 from nuclear extract severely reduced splicing activity in an in vitro splicing assay using a β-globin minigene as a substrate, while readdition of the CDK11p110 complexes restored splicing activity. Additionally, disrupting the interaction between CDK11p110 and other splicing component using a recombinant N-terminal 50 amino acids fragment of the CDK11p110 protein kinase greatly reduced splicing activity (Hu et al. 2003). Ectopic expression of cyclins L1α, L1β, L2α, L2β, or catalytically active CDK11p110 proteins individually enhances intron splicing activity, while expression of catalytically inactive form of CDK11, CDK11p110DN, CDK11p58, or CDK11p46 represses splicing activity when using the pTN24 transcription/splicing dual in vivo reporting system. More importantly, coexpression of cyclin Lα and Lβ and CDK11p110 alters constitutive splicing of the TN24 plasmid and alternative splicing of the E1A minigene reporter in vivo (Loyer et al. 2008). CDK11p110 and 9G8 also appear to be involved in mRNA 3′-end processing based on a recent study which showed that CDK11 and 9G8 are involved in regulating HIV-1 mRNA 3′-end processing. These investigators also found that the eukaryotic initiation factor 3 subunit f (eIF3F) can block the 3′ mRNA processing by altering the 3′ end pre-mRNA sequence recognition by 9G8 coupled with CDK11 (Valente et al. 2009). Taken together, these data indicates CDK11p110 protein kinase activity plays crucial role in pre-mRNA splicing processing possibly by coupling mRNA processing with transcription.

CDK11 and Mitosis

CDK11p58 is specifically expressed during the G2/M phase of the cell cycle from the same mRNA that produces CDK11p110 via an internal ribosome entry site (IRES) sequence in the coding region of the transcript (Cornelis et al. 2000). This uniquely regulated expression strongly suggested that CDK11p58, most likely in association with cyclin L. proteins, functions during mitosis. Defects in IRES directed cap-independent translation during mitosis (e.g., lack of translation of the IRES regulated protein 14–3-3σ) leads to reduced CDK11p58 expression and mitotic defects, such as the absence of polo-like kinase 1 (Plk1) at the midbody, the impairment of cytokinesis, and the accumulation of binucleated cells (Wilker et al. 2007). Further evidence that CDK11p58 expression is tightly regulated during G2/M comes from studies showing that minimal overexpression of CDK11p58 in CHO (Chinese hamster ovary) cells resulted in aneuploidy, a delay in cytokinesis exemplified by the presence of a large number of cells with tubulin midbodies, telophase defects, and apoptosis (Lahti et al. 1995; Bunnell et al. 1990). More recent studies using siRNAs targeting CDK11 have shown that CDK11p58 is required for proper mitosis (Petretti et al. 2006; Hu et al. 2007). Moderate depletion of CDK11 expression in Hela cells using siRNAs targeting CDK11 causes misaligned chromosomes but does not prevent mitotic progression. Further diminution of CDK11 expression leads to centrosome morphological defects, centrosome number abnormalities, abnormal mitotic spindle, defective chromosome congression as well as premature sister chromatid separation, permanent mitotic arrest, and cell death. Importantly, the mitotic defects caused by CDK11 depletion can be rescued, at least in part, by ectopic expression of GFP-CDK11p58 (Hu et al. 2007; Petretti et al. 2006).

These studies and immunofluorescence experiments also revealed that CDK11 associates with centrosomes throughout the cell cycle, but that the association intensity is increased as the mitotic spindles form and the chromosomes congress. Staining is then reduced as the cells enter anaphase (Petretti et al. 2006). Studies in Xenopus system have also shown that CDK11 localizes on spindle poles and microtubules, stabilizes microtubules in RanGTP-dependent manner, and that CDK11 kinase activity is important for spindle assembly and function (Yokoyama et al. 2008).

CDK11 depletion also causes spindle checkpoint activation and mitotic arrest. The spindle checkpoint machinery does not function properly when CDK11 is depleted since sister chromatids are able to partially separate and BubR1 (a mitotic checkpoint regulatory serine/threonine-protein kinase) is retained on the separated kinetochores. Moreover, immunofluorescence studies on CDK11 RNAi-treated cells showed that the cohesion subunit Scc1 prematurely dissociates from the kinetochores and the localization of the cohesion guardian Sgo1 at the kinetochore region is altered (Hu et al. 2007). These data support the conclusion that CDK11 plays a crucial role in the regulation of sister chromatid cohesion.

Finally, CDK11 gene knockout studies demonstrate a role for CDK11 in mitosis during development. Deletion of the mouse Cdk11 gene resulted in embryonic lethality at E3.5. The CDK11-deficient blastocyst cells exhibited cell proliferation defects (as judged by the low level of BrdU incorporation) and mitotic arrest (illustrated by staining with Histone 3 phosphor-Ser10 antibody) (Li et al. 2004), indicating at least one isoform of the CDK11 protein kinase is involved in mitotic regulation.

CDK11 and Apoptosis

The early hypothesis that CDK11 might function in apoptosis was based on the discovery of the CDK11p46 isoform. This 46 kD isoform is generated by caspase-dependent cleavage of the preexisting pools of CDK11p110 and CDK11p58 upon the induction of apoptosis. CDK11p46 contains the intact kinase catalytic domain but lacks the N-terminal region of p110 and the N-terminal 52 amino acids that are present in the CDK11p58 isoform (Lahti et al. 1995; Beyaert et al. 1997). The production of these isoforms may be regulated by phosphorylation since phosphorylation of CDK11p110 is coupled with caspase cleavage during Fas-mediated cell death (Tang et al. 1998). Ectopic expression of the kinase active form of CDK11p46, not the inactive form, in CHO cells induces apoptosis (Lahti et al. 1995). It has also been reported that CDK11p46 induces anoikis, a special form of apoptosis caused by disruption of cell–matrix interactions, and associates with PAK1 (p21-activated kinase 1) leading to the inhibition of PAK1 kinase activity (Chen et al. 2003). Other studies demonstrated that CDK11p46 interacts with and phosphorylates elF3f, a subunit of eukaryotic elongation factor 3. The phosphorylation of elF3f enhances its association with the core elF3 complex during apoptosis, suggesting that phosphorylation of this protein by CDK11p46 may inhibit protein translation by enhancing the binding of elF3f to the elF3 core during apoptosis (Shi et al. 2009). Like the other larger CDK11 isoforms, CDK11p46 associates with cyclin L1α, L2α, and L2β, although it is not clear whether this association regulates CDK11p46 function. Taken together the data mentioned above suggest that CDK11p46 is involved in apoptotic signaling pathway, like p34cdc2 (Shi et al. 1994).

CDK11 and Tumorigenesis

Given the many important biological functions observed thus far for CDK11, it is very logical to speculate that any genetic abnormalities for CDK11 gene and its regulation defects could lead to severe human disease. Indeed, deletion of one allele of 1p36.3 chromosome region, which contains the two human CDK11 genes, is often observed in human tumors, including neuroblastoma, melanoma, colon cancer, ovarian cancer, breast cancer, and pheochromocytoma (reviewed in Trembley et al. 2004). Although the Cdk11+/− heterozygous mice have normal development (Li et al. 2004) indicating that loss of Cdk11 alone is not sufficient for tumorigenesis, when Cdk11 heterozygous and control mice were challenged with skin cancer inducing carcinogens there was a threefold increase in the number of tumors per mouse and an increased frequency of larger papillomas in Cdk11 heterozygous mice as compared to wild-type mice (Chandramouli et al. 2007). Furthermore, a 2.5-fold downregulation of Cdk11 gene expression was found in the invasive mouse skin carcinomas in association with mutant p53 and mutant H- ras status (Zhang et al. 2005). Another line of evidence implicating CDK11 in tumorigenesis comes from the discovery that CDK11 regulates the Hh (hedgehog) signaling pathway. Disruption or improper activation of this pathway is associated with developmental abnormalities and tumorigenesis (Evangelista et al. 2008). CDK11 was also identified as a kinase regulator for Wnt/β-catenin signaling pathway in a high-throughput siRNA screening (Naik et al. 2009). These studies showed that decreasing CDK11 expression resulted in reduced β-catenin-dependent transcription suggesting that CDK11 could be a potential therapeutic target in tumors with dysregulation of Wnt/β-catenin signaling, for example, colorectal cancer, breast cancer, and hepatocellular carcinoma (Clevers 2006).

Loss of CDK11 also causes defects in cell cycle, especially during mitosis. Cell cycle misregulation is one of the hallmarks of cancer cells. As mentioned above, the G2/M-specific CDK11p58 isoform regulates mitotic progression (Petretti et al. 2006; Hu et al. 2007). Defects in IRES directed cap-independent translation machinery, which is responsible for generating most of the proteins that are produced during late G2 and mitosis, cause reduced CDK11p58 expression and which results in mitotic abnormalities and in turn contributes to aneuploidy and tumorigenesis (Wilker et al. 2007). Expression of the Myc oncogene in Eμ-Myc/+ mice disrupts IRES-mediated translation of proteins during mitosis and leads to tumor formation (Barna et al. 2008). Further analysis of these tumors revealed decreased CDK11p58 expression and increased aneuploidy (Barna et al. 2008). Importantly, this defect can be suppressed by restoring CDK11p58 expression to normal levels (Barna et al. 2008). These observations strongly suggest that CDK11 may be a tumor suppressor gene.

Summary

Since the discovery of CDK11 gene roughly three decades ago, studies from many labs have advanced our understanding of CDK11 gene function and regulation. Based on these studies, it is now clear that CDK11 is essential for cell growth and that the different CDK11 isoforms function in distinct cellular processes such as transcription, mRNA processing/splicing (CDK11p110), mitotic progression (CDK11p58), apoptosis (CDK11p46), and tumorigenesis (Table 1). More detailed analysis is needed to establish the roles of the various CDK11 isoform in vivo and the roles in tumorigenesis. Likewise, although CDK11 protein kinases associate with cyclin L1 and L2, and coexpression of L. cyclins and CDK11p110 strongly affect alternative splicing and results in differences in the number and type of transcripts that are produced by alternate splicing in comparison with expressing those proteins individually (Loyer et al. 2008), the detailed regulatory mechanisms on their cooperative and synergistic activities remain to be clarified. Current studies are also highly focused on identifying CDK11 kinase substrates. Since CDK11 protein kinases have multiple functions in different cellular processes, the identification of more bona fide substrates is a key step in improving our understanding of the function and regulation of the various CDK11 isoforms. To date, 9G8 and elF3f are the only substrates that have been studied extensively. However, the exact CDK11p110 phosphorylation site(s) on 9G8 and the functional relevance of this phosphorylation are yet to be elucidated. The other challenge in understanding CDK11 function is generating appropriate molecular tools to define or discriminate between the many different CDK11 protein isoforms and splice variants and to determine their functions in various signaling pathways. Additionally, determining how CDK11 influences tumorigenesis remains an important question for further investigation. Generating CDK11 mouse models that allow modulation of CDK11 expression in specific tissues is necessary to understand the role of CDK11 in tumorigenesis and to address the possibility of developing CDK11-specific protein kinase inhibitors for the therapeutic purposes.
CDK11, Table 1

The major functions of different CDK11 protein isoforms

CDK11 proteins

Major functions

CDK11p110

Transcription

RNA processing/splicing

Hh signaling

Wnt/β-catenin signaling

Other functions?

CDK11p58

Mitosis progression

Centrosome function

Spindle formation and functioning

Sister chromatid cohesion

Spindle checkpoint control

Chromosome congression

Other functions?

CDK11p46

Apoptosis

Other functions?

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of SurgerySt. Jude Children’s Research HospitalMemphisUSA
  2. 2.Department of Tumor Cell BiologySt. Jude Children’s Research HospitalMemphisUSA