Cyclin-dependent kinase 4


DEVELOPMENTAL BIOLOGY

Embryonic

Like vertebrate cdk4 and cdk6, Drosophila cdk4 binds also to a D-type cyclin according to the results of two-hybrid experiments in yeast. Northern blot analysis indicates that Drosophila kinases are expressed throughout embryogenesis. Expression in early embryogenesis appears to be ubiquitous according to in situ hybridization (Sauer, 1996).

Effects of Mutation or Deletion

Surprisingly, homozygous Cdk43 mutant progeny from heterozygous parents develop into adult flies that eclose without a developmental delay. While the fertility of homozygous females is severely reduced, occasional progeny can be obtained even from homozygous parents demonstrating that Cdk4 is not absolutely essential for cell proliferation or development to the adult stage (Datar, 2000).

Interestingly, homozygous Cdk43 flies are found to be significantly smaller than wild-type flies. Size reduction affects all aspects of the flies proportionally. The weight of Cdk43 homozygotes is found to be ~20% lower than that of heterozygotes. The wing area of Cdk43 homozygotes is found to be ~10% lower than that of heterozygotes. Since each cell is known to secrete one hair during wing development, the hair density was determined in a defined region of the adult wings as a measure of cell size. The results indicate that the cells in wings of Cdk43 homozygotes are slightly larger compared with heterozygotes. The values determined for the total wing size and for the cell size were used to extrapolate the total cell number present in the wing. These estimations indicate that the wings of Cdk43 homozygotes contained fewer cells than those of heterozygotes (Meyer, 2000).

To demonstrate that the decrease in weight, wing size and cell numbers observed in Cdk43 homozygotes is caused by loss of Cdk4 function and not by potential second site mutations on the chromosome, UAS-Cdk4 was expressed ubiquitously in Cdk43 homozygotes with the help of da-GAL4. This prevented the reduction in weight, wing size and cell numbers. Analogous ubiquitous expression of mutant Cdk4D175N- myc has essentially no effect in Cdk43 homozygotes. The D175N mutation affects an aspartate residue that is conserved in all protein kinases and known to be required for the phosphotransfer reaction. Overexpression of cdk1 and cdk2 with analogous mutations results in dominant-negative inhibition of the corresponding endogenous cdks in mammalian cells. Mutant Cdk4D175N-myc protein binds to Cyclin D with the same efficiency as Cdk4-myc and thus is expected to act in a dominant-negative manner. While Cdk4D175N-myc expression does not reduce the weight of Cdk43 mutants, it results in a slight but significant weight decrease in Cdk4+ flies. In additional experiments, a comparision was made of the effects of Cdk4D175N-myc expression on the weight of Cdk43 homo- and hetero-zygotes that had developed in the same bottle. These experiments clearly confirm that UAS-Cdk4D175N-myc reduces fly weight when expressed in Cdk43 heterozygotes, while it has at most the opposite effect in Cdk43 homozygotes. The fact that dominant-negative Cdk4 has no effect in Cdk43 flies argues strongly that Cdk4 is the only Cyclin D-dependent cdk in Drosophila. It is emphasized that this conclusion is complicated but not invalidated by the possibility that Cdk4 might not only act as a protein kinase but also by titrating putative INK inhibitors as described for mammalian cdk4/6. However, the Drosophila genome sequence has no INK orthologs (Meyer, 2000).

To analyze the effects of loss of Cdk4 function on cell growth and cell cycle progression, the behavior of homozygous Cdk43 was compared with wild-type sister clones induced by mitotic recombination. Sixty-seven hours after clone induction, the area covered by Cdk43 clones in imaginal wing discs was only about two-thirds of the area covered by sister clones. Analysis by flow cytometry revealed no significant differences in either cell size or in the cell cycle profile. In addition, no pyknotic nuclei were observed in Cdk43 mutant clones, suggesting that cell death does not play a significant role in the reduced growth of Cdk43 mutant clones. These data indicate that Cdk43 cells grow slowly and that their cell cycle is lengthened by a proportionate increase in the G1, S and G2 phases (Meyer, 2000).

In addition to D-type cyclin-cdk complexes, cyclin E-cdk2 has also been implicated in the regulation of cell cycle progression through the G1 phase. The presence of Cyclin E-Cdk2 might explain the relatively mild phenotype observed in flies lacking Cdk4 function. To evaluate this notion, the effects of heterozygosity for Cyclin E and Cdk2 mutations was studied in Cdk4 mutants. While heterozygosity for mutations in Cyclin E is readily tolerated in Cdk43 heterozygotes, it results in complete lethality in Cdk43 homozygotes. Similarly, heterozygosity for mutations in Cdk2 results in an almost complete lethality in Cdk43 homozygotes, while it has no effect in Cdk43 heterozygotes. In contrast, mutations in Cyclin A, Cyclin B, Cyclin B3 and Cdk1 have no effect on the survival of Cdk43 homozygotes. These observations demonstrate that Cdk4 mutants are particularly sensitive to reduction in Cyclin E-Cdk2 levels (Meyer, 2000).

Vertebrate D-type cyclin-cdk complexes inhibit Rb function. The defects observed in Cdk4 mutants, therefore, might reflect increased Rb function. To evaluate this notion, the effects were studied of heterozygosity for mutations in the gene encoding the Drosophila Rb family member (RBF) on the fertility and size of Cdk4 mutant females. For these experiments two putative null alleles, RBF11 and RBF14, were used. A PCR assay was developed to monitor the presence of the RBF11 allele. Cdk4 mutant females heterozygous for RBF11 (RBF11/+; Cdk43/Cdk43) were found to be significantly more fertile than sibling females without RBF11 (+/+; Cdk43/Cdk43). In the experiment with RBF14, the presence of this mutation could not be monitored. Based on the crossing scheme, however, one half of the Cdk4 mutant females were expected to be heterozygous for RBF14 (RBF14/+; Cdk43/Cdk43), while the other half was expected to have two functional RBF gene copies (+/+; Cdk43/Cdk43). As in the RBF11 experiment, an increased fertility was observed in ~50% of the Cdk4 mutant females in the RBF14 experiment. Therefore, the 50% of females with increased fertility presumably correspond to the RBF14 heterozygotes. It is concluded that the fertility of Cdk4mutant females is increased by a reduction from two to one in the copy number of functional RBF genes. Similarly, heterozygosity for mutations in RBF was found to increase the weight of Cdk4 mutant females. The antagonistic activities of Cdk4 and RBF could also be demonstrated in experiments involving overexpression using the UAS-GAL4 system (Meyer, 2000).

Cyclin D does not provide essential Cdk4-independent functions in Drosophila

The three mammalian D-type cyclins are thought to promote progression through the G1 phase of the cell cycle as regulatory subunits of cyclin-dependent kinase 4 and 6. In addition, they have been proposed to control the activity of various transcription factors without a partner kinase. This study describes phenotypic consequences of null mutations in Cyclin D, the single D-type cyclin gene in Drosophila. As previously observed with null mutations in the single Drosophila Cdk4 gene, these mutations do not primarily affect progression through the G1 phase. Moreover, the apparently indistinguishable phenotypes of double (CycD and Cdk4) and single mutants (CycD or Cdk4) argue against major independent functions of Cyclin D and Cdk4. The reduced cellular and organismal growth rates observed in both mutants indicate that Cyclin D-Cdk4 acts as a growth driver (Emmerich, 2004).

D-type cyclin-cdk complexes are of crucial importance in human tumorigenesis. Since these complexes have been conserved in evolution, it is readily possible to use model organisms like D. melanogaster for functional characterizations. This study extends previous characterization of Drosophila Cdk4 mutants by phenotypic comparisons with CycD mutants. As observed for Cdk4, Cyclin D is not required for progression through the G1 phase of the cell cycle. Some escapers develop to the adult stage even when both maternal and zygotic Cdk4+ or CycD+ function is abolished. Moreover, FACS analyses demonstrate that the cell-cycle profile of wing-imaginal disc cells homozygous for null mutations in Cdk4 or CycD is essentially indistinguishable from that of wild type. The evidence therefore is not consistent with the prevailing idea that D-type cyclin-cdk complexes primarily regulate progression through the G1 phase. In cultured mammalian cells, where the most support for this suggestion has accumulated, D-type cyclin-cdk complexes have been shown to act in part by titrating CIP/KIP inhibitors away from CycE/Cdk2 complexes, which are thus freed to stimulate cell-cycle progression. In contrast, binding of Dacapo, the single known Drosophila CIP/KIP family member, to Drosophila Cyclin D-Cdk4 has not been detectable. This provides a potential explanation for the apparent discrepancy. It should be noted, however, that the strong genetic interactions reported among CycD, CycE, and Cdk2, previous interaction tests performed with Rbf indicate that Drosophila CyclinD-Cdk4 complexes do play a significant, if redundant, activating role in the E2F/RBF network, just as described in mammals. In the CycD and Cdk4 mutants, CycE/Cdk2 complexes are presumably sufficient to perform this function (Emmerich, 2004).

While not revealing a specific role during G1, the Drosophila mutant phenotypes provide compelling evidence that Cyclin D-Cdk4 promotes cellular growth and thereby accelerates progression through all the cell-cycle phases proportionally. CycD and Cdk4 mutants develop into small but normally proportioned flies with an average weight of ~20% less than that of wild-type siblings. Conversely, overexpression of Cyclin D and Cdk4 has the opposite effect, causing increased growth in organs such as the eye, wing, and salivary glands. Moreover, growth regulation by Cyclin D and Cdk4 is also clearly apparent at the cellular level. Clones of wing-imaginal disc cells either lacking one of the Cyclin D-Cdk4 complex partners or overexpressing the complex grow slower or faster, respectively, than wild-type clones (Emmerich, 2004).

In Drosophila, the growth-promoting function of Cyclin D-Cdk4 can be interrogated using genetic approaches. Initial results have so far argued that Cyclin D-Cdk4 is not part of one of the other pathways (insulin/TOR, ras, myc, bantam), which are known to control cellular and organismal growth rates. However, the Hif-1 prolyl hydroxylase has been identified as a key growth stimulator downstream of Cyclin D-Cdk4. This raises the possibility that Cyclin D-Cdk4 is interconnected with metabolic pathways sensitive to oxygen levels. Future analyses might therefore reveal whether an involvement in oxygen-related metabolism represents the evolutionary conserved role of Cyclin D-Cdk4 in multicellular eukaryotes and throw a new light on its significance in human tumors, where oxygen limitation is a known and crucial challenge. Cyclin D-Cdk4 has also recently been implicated in the JAK-STAT pathway by an independent genetic approach in Drosophila (Emmerich, 2004 and references therein).

This comparison of CycD and Cdk4 mutant phenotypes is also of interest with regard to functions provided by these proteins independently. In particular, D-type cyclins have been proposed to regulate a number of transcription factors without a partner kinase. Moreover, overexpression of UAS-CycD alone or UAS-Cdk4 alone does often have phenotypic consequences that vary in extent with different GAL4 driver lines. For instance, ey-GAL4-driven UAS-CycD expression suppresses the inhibitory effects of simultaneous UAS-RBF1 expression dramatically. Similarly, da-GAL4-driven UAS-CycD expression during development of otherwise wild-type flies results in an increased adult fly weight. However, in these experiments in Drosophila, the overexpressed Cyclin D might execute its effect in combination with excess Cdk4 expressed from the endogenous Cdk4 gene, as suggested by the finding that da-GAL4-driven UAS-CycD expression in Cdk4 mutants increases adult fly weight at most marginally. The findings that loss of CycD+ or Cdk4+ function, as well as simultaneous loss of both CycD+ and Cdk4+ function, results in essentially indistinguishable phenotypes and does not necessarily prevent development to the adult stage, demonstrate that neither Cyclin D nor Cdk4 provides essential functions in Drosophila independently of each other (Emmerich, 2004).

The Drosophila mitochondrial ribosomal protein mRpL12 is required for Cyclin D/Cdk4-driven growth

The Drosophila cyclin-dependent protein kinase complex CycD/Cdk4 stimulates both cell cycle progression and cell growth (accumulation of mass). CycD/Cdk4 promotes cell cycle progression via the well-characterized RBF/E2F pathway, but an understanding of how growth is stimulated remains limited. To identify growth regulatory targets of CycD/Cdk4, a loss-of-function screen was performed for modifiers of CycD/Cdk4-induced overgrowth of the Drosophila eye. One mutation that suppresses CycD/Cdk4 was in a gene encoding the mitochondrial ribosomal protein, mRpL12. mRpL12 is required for CycD/Cdk4-induced cell growth. Cells homozygous mutant for mRpL12 have reduced mitochondrial activity, and exhibit growth defects that are very similar to those of cdk4 null cells. CycD/Cdk4 stimulates mitochondrial activity, and this is mRpL12 dependent. Hif-1 prolyl hydroxylase (Hph), another effector of CycD/Cdk4, regulates growth and is required for inhibition of the hypoxia-inducible transcription factor 1 (Hif-1). Both functions depend on mRpL12 dosage, suggesting that CycD/Cdk4, mRpL12 and Hph function together in a common pathway that controls cell growth via affecting mitochondrial activity (Frei, 2005 ).

Mitochondria are required for the synthesis of ATP, as well as for many biological functions. Most mitochondrial proteins are encoded by nuclear genes, and are imported into mitochondria. The mitochondrial DNA contains only a handful of genes, encoding several subunits of enzymes required for oxidative phosphorylation. Therefore, translation of mitochondrial-encoded mRNAs is a prerequisite of mitochondrial function and thus ATP synthesis. However, an understanding of how mitochondrial protein synthesis is regulated and how it is regulated in response to nuclear genes is still limited (Frei, 2005).

Mammalian MRPL12 was the first mitochondrial ribosomal protein to be characterized, and is encoded by a nuclear gene. The protein forms a homodimer, localizes predominantly to mitochondria and binds to the large mitochondrial ribosomal subunit. In cultured cells, MRPL12 mRNA levels are induced by the addition of serum, and ectopic expression of a truncated version leads to reduced ATP synthesis and reduced growth. In bacteria, ribosomal proteins L7 and L12 are orthologs of MRPL12. L7 is identical to L12, except for an N-terminal acetyl group. The two proteins form a dimer and localize to a special structure on the large ribosomal subunit. This structure, the 'ribosomal stalk', is composed of two L7/L12 dimers, as well as the L10 protein, and is required for the recruitment of translation elongation factors Tu and G to the large ribosomal subunit. Therefore, L7/L12 are essential for mitochondrial protein synthesis, and thus for the generation of ATP (Frei, 2005).

The Drosophila genome encodes one mitochondrial L7/L12 homolog: mRpL12. This protein was first identified for its localization to mitochondria-type ribosomes in the germ plasm of Drosophila embryos. mRpL12 is required for CycD/Cdk4 to drive cell growth. Importantly, the mRpL12 mutant showed no dominant suppression of other growth drivers, like dMyc or the insulin signaling pathway, suggesting that the suppression is specific for CycD/Cdk4. Cells lacking mRpL12 have strongly reduced MitoTracker and COX stainings. This suggests that the inner-mitochondrial membrane potential is reduced, presumably due to a decrease in the translation of mitochondrial-encoded subunits of the electron transport chain. Therefore, mRpL12 might have a function similar to bacterial L7/L12 (Frei, 2005).

The data show that CycD/Cdk4 stimulates mitochondrial activity, and that this increase is required for the stimulation of cellular growth. This induction requires mRpL12, suggesting that mitochondrial protein synthesis might be regulated in response to CycD/Cdk4. It is still not known how this is achieved. The data do not exclude the possibility that mRpL12 has a function outside mitochondria, and that loss of this function causes suppression of CycD/Cdk4-stimulated growth. However, this seems very unlikely, since almost perfect colocalization of mRpL12-GFP with mitochondria was seen, and mitochondrial activity correlates well with CycD/Cdk4-driven growth (Frei, 2005).

Whether other mutants, defective for mitochondrial ribosomes would suppress CycD/Cdk4-driven overgrowth phenotypes was also tested. The only other characterized mutant, bonsaï (mRpS15), did not suppress CycD/Cdk4-driven overgrowth in the eye when heterozygous. Furthermore, several lines predicted to be specific mutants for mRpL4, mRpL15, mRpL17 and mRpS32 were tested but none suppressed CycD/Cdk4 in heterozygous conditions. Although none of the latter mutants are characterized, these data suggest that mRpL12 might be special among mitochondrial ribosomal proteins in its ability to suppress the action of CycD/Cdk4. Since tests were performed in heterozygotes, this is not surprising; mRpL12 may be the only one of these components that is dosage-limiting for the activity of mitochondrial ribosomes. Alternatively, mRpL12 might uniquely be targeted by CycD/Cdk4. Nevertheless, the finding that CycD/Cdk4-driven growth is significantly reduced by the mitochondrial inhibitors rotenone and antimycin A supports the requirement of mitochondria (Frei, 2005).

Mammalian Hif prolyl hydroxylases (HPHs) are required for the cellular response to hypoxia. These enzymes hydroxylate Hif-1alpha, leading to its ubiquitin-dependent degradation. Cells lacking Drosophila Hph have increased Hif-1alpha/Sima protein levels and transcriptional activity, demonstrating that fly Hph is an important regulator of Hif-1alpha/Sima. It has been shown that Drosophila Hph is also required for cellular growth, a function that is likely to be independent of Hif-1alpha/Sima (Frei, 2005).

Mutants of mRpL12 and hph show very similar suppression phenotypes with respect to CycD/Cdk4. Furthermore, Hph requires mRpL12 to drive cell growth, and cells lacking mRpL12 have ectopic activation of Hif-1. This suggests that CycD/Cdk4, mRpL12 and Hph function in the same pathway. The data presented here suggest that CycD/Cdk4 could have a dual function in growth control: (1) CycD/Cdk4 stimulates mitochondrial activity, in an mRpL12-dependent but Hph-independent manner; (2) Hph protein is regulated post-transcriptionally in response to CycD/Cdk4. Moreover, cells lacking mRpL12 have normal Hph protein levels, but increased Hif-1 activity. This suggests that Hph's hydroxylation activity may be regulated in response to the mitochondrial activity (Frei, 2005).


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Cyclin-dependent kinase 4: Biological Overview | Evolutionary Homologs | Regulation | Developmental Biology | Effects of Mutation

date revised: 10 August 2010

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