Gene name - kayak
Synonyms - D-Fos, Fos-related antigen, Fra
Cytological map position - 99B9--99B10
Function - transcription factor
Symbol - kay
FlyBase ID: FBgn0001297
Genetic map position - 3-
Classification - basic leucine zipper
Cellular location - nuclear
|Recent literature||Kulshammer, E., Mundorf, J., Kilinc, M., Frommolt, P., Wagle, P. and Uhlirova, M. (2015). Interplay among Drosophila transcription factors Ets21c, Fos and Ftz-F1 drives JNK-mediated tumor malignancy. Dis Model Mech 8: 1279-1293. PubMed ID: 26398940
This study defines TF network that triggers an abnormal gene expression program promoting malignancy of clonal tumors, generated in Drosophila imaginal disc epithelium by gain of oncogenic Ras (RasV12) and loss of the tumor suppressor Scribble (scrib1). Malignant transformation of the rasV12scrib1 tumors requires TFs of distinct families, namely the bZIP protein Fos, the ETS-domain factor Ets21c and the nuclear receptor Ftz-F1, all acting downstream of Jun-N-terminal kinase (JNK). Depleting any of the three TFs improves viability of tumor-bearing larvae, and this positive effect can be enhanced further by their combined removal. Although both Fos and Ftz-F1 synergistically contribute to rasV12scrib1 tumor invasiveness, only Fos is required for JNK-induced differentiation defects and Matrix metalloprotease (MMP1) upregulation. In contrast, the Fos-dimerizing partner Jun is dispensable for JNK to exert its effects in rasV12scrib1 tumors. Interestingly, Ets21c and Ftz-F1 are transcriptionally induced in these tumors in a JNK- and Fos-dependent manner, thereby demonstrating a hierarchy within the tripartite TF network, with Fos acting as the most upstream JNK effector. Of the three TFs, only Ets21c can efficiently substitute for loss of polarity and cooperate with Ras(V12) in inducing malignant clones that, like rasV12scrib1 tumors, invade other tissues and overexpress MMP1 and the Drosophila insulin-like peptide 8 (Dilp8). While rasV12ets21c tumors require JNK for invasiveness, the JNK activity is dispensable for their growth. In conclusion, this study delineates both unique and overlapping functions of distinct TFs that cooperatively promote aberrant expression of target genes, leading to malignant tumor phenotypes.
|Klein, J. D., Qu, C., Yang, X., Fan, Y., Tang, C. and Peng, J. C. (2016). c-Fos repression by Piwi regulates Drosophila ovarian germline formation and tissue morphogenesis. PLoS Genet 12: e1006281. PubMed ID: 27622269
Drosophila melanogaster Piwi functions within the germline stem cells (GSCs) and the somatic niche to regulate GSC self-renewal and differentiation. How Piwi influences GSCs is largely unknown. This study uncovered a genetic interaction between Piwi and c-Fos in the somatic niche that influences GSCs. c-Fos is a proto-oncogene that influences many cell and developmental processes. In wild-type ovarian cells, c-Fos is post-transcriptionally repressed by Piwi, which destabilized the c-Fos mRNA by promoting the processing of its 3' untranslated region (UTR) into Piwi-interacting RNAs (piRNAs). The c-Fos 3' UTR was sufficient to trigger Piwi-dependent destabilization of a GFP reporter. Piwi represses c-Fos in the somatic niche to regulate GSC maintenance and differentiation and in the somatic follicle cells to affect somatic cell disorganization, tissue dysmorphogenesis, oocyte maturation arrest, and infertility.
|Chen, L., Nye, D.M., Stone, M.C., Weiner, A.T.,
Gheres, K.W., Xiong, X., Collins, C.A. and Rolls, M.M. (2016). Mitochondria and caspases tune Nmnat-mediated stabilization to promote axon
regeneration. PLoS Genet 12: e1006503. PubMed ID: 27923046
Axon injury can lead to several cell survival responses including increased stability and axon regeneration. Using an accessible Drosophila model system, this study investigated the regulation of injury responses and their relationship. Axon injury stabilizes the rest of the cell, including the entire dendrite arbor. After axon injury, it was found that mitochondrial fission in dendrites is upregulated, and reducing fission increases stabilization or neuroprotection (NP). Thus axon injury seems to both turn on NP, but also dampen it by activating mitochondrial fission. Caspases were identified to be negative regulators of axon injury-mediated NP, so mitochondrial fission could control NP through caspase activation. In addition to negative regulators of NP, it was found that nicotinamide mononucleotide adenylyltransferase (Nmnat) is absolutely required for this type of NP. Increased microtubule dynamics, which has previously been associated with NP, requires Nmnat. Indeed Nmnat overexpression is sufficient to induce NP and increase microtubule dynamics in the absence of axon injury. DLK, JNK and fos are also required for NP. Because NP occurs before axon regeneration, and NP seems to be actively downregulated, it was tested whether excessive NP might inhibit regeneration. Indeed both Nmnat overexpression and caspase reduction reduce regeneration. In addition, overexpression of fos or JNK extend the timecourse of NP and dampen regeneration in a Nmnat-dependent manner. These data suggest that NP and regeneration are conflicting responses to axon injury, and that therapeutic strategies that boost NP may reduce regeneration.
Drosophila kayak, better known as Fos-related antigen (Fra), or, as the gene is known in mammals, FOS, is a basic leucine zipper protein. In mammalian cells, another basic leucine zipper protein called JUN interacts with FOS. Mammalian JUN is also a transcription factor and oncogene. It is activated through RAS/MAPK-mediated phosphorylation. AP-1 is a FOS-JUN heterodimer that serve to activate genes involved in neural function and the immune response. Multiple FOS and JUN proteins are found in mammals. Most of the genes encoding AP-1 components behave as "immediate early" genes, that is, genes whose transcription is rapidly induced following cell stimuation, independent of de novo protein synthesis.
Fos-related antigen/kayak plays a critical role during Drosophila endoderm induction. Fra is required downstream from Decapentaplegic signaling for the regulation of labial. Expression of labial in the midgut coincides with copper cells. Labial has a role not only in determination and differentiation of copper cells, but also in the maintenance of their differentiated state. Copper cells are specialized endodermal cells that may function to adsorb metal ions from the gut lumin (Hoppler, 1994).
As there are no Fra mutants, nor any genomic deletions in the region encoding Fra, a dominant-negative approach was used to interfere with Fra function. A truncated version of Fra (Fbz) was used (Eresh, 1997). Fbz consists of the basic region leucine zipper (bZIP) domain only. Fbz could be expected to act in a dominant negative fashion as it consists merely of the domain which confers DNA binding and dimerization. The Gal4 system was used to express Fbz. In this system, dominant negative Fbz was expressed from a UAS promoter drive by Gal4 expression in the endoderm. Other bZIP versions of Jun related antigen (Jbz) and CrebB-17A (Cbz) were likewise expressed in the midgut. The number of copper cells in the Fbz-expressing larvae were strikingly reduced, albeit somewhat variably; in most first instar larvae, the band of copper cells was shortened to a rudimentary domain, approximately 20-40% of normal length, whereas in about 5% of the Fbz-expressing larvae, copper cells were missing altogether. Cbz-expressing larvae also showed shortened copper cell domains, although the degree of interference with copper cell development in this case was significantly milder than in Fbz-expressing larvae. No copper cell phenotypes were observed after expression of Jbz, nor after overexpression of any of the full-length proteins Fra, Jra or CrebB-17A. It is important to note that Fra is capable of activating copper cell development by itself, without the help of Jra. Ectopic expression of Fbz appears to result in an overabundance of large flat cells instead of copper cells or interstitial cells (Riese, 1997).
There are two explanations for why Fbz interferes with cell differentiation in the larval gut: either Fra is required in parallel to, and independently of, labial for copper cell development, or Fra acts through labial, by stimulating its expression, to promote copper cell development. The number of labial expressing cells is much reduced in Fzb-expressing larvae. It follows that Fbz must have an effect on labial induction as early as this induction can be detected. Jbz has no effect on labial when expressed the same way. These results suggest an early function of Fra during labial induction. It is important to note the Fra, like Lab itself, is still required to maintain lab expression during larval development, long after the inducing signals have disappeared, suggesting a function for Fra in the cellular memorization of the signal-induced active state of labial transcription (Riese, 1997).
Previous studies have shown that endodermal labial expression is also induced by Decapentaplegic signaling (from the mesoderm) to high expression levels in the same section of the embryonic endoderm (for example, see Eresh, 1997). labial is not only stimulated by Dpp, but is controlled both positively and negatively by wingless, depending on Wg levels (Hoppler, 1995). It would seem that Fra is expressed in all endodermal cells while labial expression is more focused. A surprising difference is revealed by embryos mutant for schnurri. labial expression is abolished in schnurri mutants (Dpp acts through schnurri). In contrast, Fra induction is just as strong in shn mutants as in wild type. The numerous differences between Fra and labial induction strongly indicate that although the two genes are induced by Dpp signaling, their inductions occur separately and in parallel to one another (Riese, 1997).
Why are multiple signals required for labial induction when, in theory, only one would suffice? There may be two answers to this question: (1) the more ubiquitously expressed Fra acts to potentiate cells to respond to Dpp and Wg signals. Without Fra, Dpp and Wg signals would fall on a population of cells lacking competence to respond. (2) Fra may be required to ensure maintenance of labial expression long after Dpp and Wg signals have disappeared. Perhaps Fra is responsible for the maintenance of copper cell fate as well as its initiation. Fra seems to be involved in a process of stepwise refinement of positional information. This is reminiscent of early embryonic patterning events where morphogen gradients of transcription factors loosely define the expression domains of segmentation genes whose products cooperate with morphogenic transcription factors to control more precise expression of target genes (Riese, 1997).
In the midline glia of the embryonic ventral nerve cord of Drosophila, differentiation as well as the subsequent regulation of cell number is under the control of EGF-receptor signaling. During pupal stages apoptosis of all midline glial cells is initiated by ecdysone signaling. In a genetic screen, mutations in disembodied, rippchen, spook, shade, shadow, shroud and tramtrack have been identified that all share a number of phenotypic traits, including defects in cuticle differentiation and nervous system development. Some of these genes were previously placed in the so-called 'Halloween-group' and have been shown to affect ecdysone synthesis during embryogenesis. The Halloween mutations not only affect glial differentiation but also lead to an increase in the number of midline glial cells, suggesting that during embryogenesis, ecdysone signaling is required to adjust glial cell number similar to pupal stages. A P-element-induced mutation of shroud has been isolated: it controls the expression of ecdysone inducible genes. The P-element insertion occurs in one of the promoters of the Drosophila fos gene for which an as yet undescribed complex genomic organization is presented. The recently described kayak alleles affect only one of the six different Fos isoforms. This work for the first time links ecydsone signaling to Fos function and shows that during embryonic and pupal stages similar developmental mechanisms control midline glia survival (Giesen, 2003).
Using local hopping mutagenesis, the P54 mutation was isolated that failed to complement all EMS-induced shroud alleles. Homozygous shroudP54 larvae show a severe shroud cuticle phenotype. Following precise excision of the P54 P-element insertion, wild type shroud function was restored, demonstrating that a P-element-induced shroud mutation was isolated (similarly, kayak function could be reverted by excision of the P-element). To identify the shroud locus, genomic DNA flanking the insertion site was isolated using a plasmid rescue approach. Sequence analysis and subsequent BLAST searches localized shroud to the region 99C2-3 on the right arm of chromosome 3, which is in agreement with meiotic mapping data (Giesen, 2003).
Two genes flank the insertion site of shroudP54: CG1973 encodes a predicted protein kinase that lies 12 kb upstream and kayak, encoding the Drosophila Fos homolog, lies 6 kb downstream of the P-element insertion. 500 bp downstream of the P-element localizes the transcription unit CG15507 that is shown here to represent the most 5' exon of the kay locus. A CG15507 specific probe was generated by PCR and was used in whole mount in situ hybridization to test whether the gene is expressed during embryogenesis. CG15507 RNA can be detected already in the unfertilized egg, indicating a maternal contribution. Expression stays rather uniform until the end of germband retraction, when enhanced expression can be detected in the developing nervous system. Expression in the CNS continues until later stages where elevated expression levels can be detected in the CNS midline (Giesen, 2003).
As seen from the complex organization of the kayak gene, kay1 is not likely to be a Fos null mutation but rather removes only two of the Fos isoforms. These data suggest that shroud and kayak are both mutations in the same gene, however, affecting different Fos isoforms. In order to obtain additional evidence supporting this notion attempts were made to rescue the shroud mutant phenotype by using an UAS-fos transgene and a rho-GAL4 driver strain. In shroud mutant embryos generally four to five midline glial cells are found at the dorsal surface of the ventral nerve cord. Following expression of the UAS-fos transgene, this mutant phenotype can indeed be partially rescued; glial cell number was adjusted to about three per neuromere and, more importantly, midline glial cells were associated with commissural axon tracts. In few neuromeres expression of fos results in a further reduction of the number of midline glial cells to one or two. Overexpression of fos in wild type embryos does not lead to a disruption of normal development. If shroud regulates expression of ecdysone inducible genes one might expect to at least partially suppress the disembodied mutant midline phenotype by overexpression of shroud. In support of this notion it was possible to partially rescue the midline glial cell phenotype of disembodied mutants following expression of fos in the single-minded expression pattern. Following fos expression, 3.9 midline glial cells were found per neuromere (Giesen, 2003).
Members of the so-called Halloween-group all led to a related embryonic CNS and larval cuticle phenotype. In all mutations studied in this work the segmental commissures appear fused; this is generally due to non-functional midline glial cells. shroud is shown to encode a transcriptional regulator involved in the implementation of the hormonal program (Giesen, 2003).
However, beside the overall phenotypic similarities displayed by mutants in the different genes differences were noted in the number of midline glial cells. In tramtrack and rippchen mutant embryos a reduction in the number of midline glial cells was observed. tramtrack is also a negative regulator of glial cell division. In the absence of tramtrack, additional glial cells can be detected in stage 14 embryos and only in older embryos a reduction in the number of glial cells can be observed. Interestingly, tramtrack and shroud appear to interact. In an effort to generate a tramtrack shroud double mutant it was noted that significantly fewer transheterozygous tramtrack/shroud flies eclosed. Thus, the BTB-Zn-finger proteins encoded by tramtrack may eventually be linked to Fos function (Giesen, 2003).
Initially, about six midline glial cells are generated in each abdominal neuromere. During the second half of embryogenesis the number of midline glial cells is reduced by apoptosis to three to four per neuromere. Only those glial cells that have formed extensive contacts to commissural axons are thought to survive. Indeed, when formation of commissural axons is impaired, as for example in the commissureless mutation, most midline glial cells die via apoptosis. Activation of Egfr by axon-derived Spitz and subsequent Ras/MAPK signaling in the midline glia is able to counteract apoptosis by inactivating the cell death protein Hid. Similar to the finding that the EGF receptor ligand Spitz regulates midline glia survival, the EGF-receptor ligand Vein, a Drosophila neuregulin homolog, provides trophic support for subsets of cortical glial cells. These findings parallel the survival promoting effects of neuregulin-1 on Schwann cells in the mammalian peripheral nervous system (Giesen, 2003).
Based on phenotypic similarities, tramtrack, disembodied, shroud, shadow, shade, spook and rippchen were classified as members of the tramtrack or Halloween-group. Mutations in the disembodied locus are characterized by defects in epidermal development, dorsal closure, head involution, midgut formation and CNS development. In particular, loss of disembodied function leads to an excess of midline glial cells that are not able to separate anterior and posterior commissures (Giesen, 2003).
disembodied and shadow had been molecularly identified and encode cytochrome P450-like proteins involved in the biosynthesis of ecdysteroid hormones. Expression of disembodied starts during blastoderm stages and appears slightly elevated in the neuroectoderm. disembodied expression decays during the onset of neuroblast delamination and is not found from stage 12/13 onwards, when midline glial cell migration is initiated. High levels of disembodied expression can be detected in the forming ring gland in stage 16 embryos long after the commissures have been established. Similarly, sad is expressed in a striped pattern in the ectoderm but from stage 12 onwards it cannot be detected anymore. From stage 15 onwards sad is expressed in the ring gland anlage (Giesen, 2003 and references therein).
Further phenotypic data indicate that other Halloween-group genes are also involved in the ecdysone biosynthetic pathway. Mutants do not only display the same cuticle phenotype, they also show a similar increase in the number of CNS midline glial cells. The data presented here suggest that ecdysone signaling is crucially important in antagonizing cell division of the CNS midline glial progenitor cells (Giesen, 2003).
This has been indeed found for later developmental stages. During the third larval instar stage, the midline glial cells proliferate and at the onset of puparium formation about 20 midline glial cells are found in each abdominal neuromere. Starting at mid-pupal stages, however, the midline glial cells undergo programmed cell death and cannot be detected in adult stages. The end of the proliferative phase of the midline glia correlates with increasing levels of ecdysteroids, suggesting a direct hormonal control of mitotic activity. Using mutants as well as CNS culture assays, it has been demonstrated that ecdysteroids not only stop the mitotic activity of the midline glial cells but also initiate the apoptosis program in these cells. In agreement with this finding, the Ecdysone receptor is expressed by the midline glia. A requirement for ecdysone signaling to stimulate apoptosis of the midline glial cells could not yet be addressed (Giesen, 2003).
Ecdysone is known to be the major hormone controlling metamorphosis. It acts through a heterodimer of Ultraspiracle and the Ecdysone receptor (EcR). In the absence of a ligand this complex represses transcription of target genes, whereas in the presence of a ligand, coactivators are recruited to activate transcription. In addition to regulating cell division and apoptosis of the midline glial cells, ecdysone may also be involved in the fine tuning of glial migration, and thus for the functional differentiation of the midline glia. During oogenesis, expression of taiman, which encodes a steroid hormone coactivator, initiates the migration of the so-called border cells. The loss of the ecdysone receptor may lead to a defect in midline glial cell development. Indeed ecdysone receptor mutants display some embryonic phenotypes similar to the ones shown by Halloween-group mutants (cuticle phenotype in about 20% of the mutant embryos). Surprisingly, however, no obvious nervous system defects were found in EcR mutants. This may indicate that the EcR functions in the embryonic midline glia. Similarly, the progression of the morphogenetic furrow in the developing eye requires ecdysone but not EcR function (Giesen, 2003).
Mutations in the gene shroud led to mutant phenotypes similar to mutations in disembodied and spook. While the levels of ecdysteroids are not affected in shroud mutants, the expression of an ecdysone inducible gene (IMP-E1) is almost completely abolished, suggesting that shroud may encode a transcriptional regulator implementing the correct hormonal response (Giesen, 2003 and references therein).
Thus, shroud encodes one of the several Fos isoforms. The structure of the fos gene is complex and the gene is spread over about 28 kb of genomic DNA harboring at least five different promoters directing the expression of six different Fos isoforms. Two distinct, partially complementing genetic loci have been mapped to the Drosophila fos gene. Mutations in kayak lead to a dorsal open phenotype in first instar larvae; similarly, shroud affects dorsal closure. Unlike shroud, kayak mutations do not lead to a midline glial cell phenotype. All tested EMS-induced shroud alleles only partially complement the strong kayak1 mutation. Interestingly, the P-element-induced mutation shroudP54 fails to complement the kayak 'null' allele but shows reduced viability in trans to hypomorphic kayak mutations. The observed intragenic complementation may be explained by the fact that the different mutations affect the different coding regions located in distinct 5' exons. Fos together with Jun constitutes the AP-1 transcription factor that is implied in a number of processes during Drosophila development. Fos as well as Jun is activated via the phosphorylation by Jun-kinase (JNK). Interestingly, JNK signaling has been implicated in apoptosis and activation of JNK signaling induces cell death via transcriptional activation of the pro-apoptotic genes reaper, grim and hid. Similarly, AP-1 function is linked to the control of apoptosis in vertebrates. It will be interesting to determine in the future how Fos will integrate in the ecdysone response during development (Giesen, 2003).
Frizzled (Fz)/PCP signaling regulates planar, vectorial orientation of cells or groups of cells within whole tissues. Although Fz/PCP signaling has been analyzed in several contexts, little is known about nuclear events acting downstream of Fz/PCP signaling in the R3/R4 cell fate decision in the Drosophila eye or in other contexts. This study demonstrates a specific requirement for Egfr-signaling and the transcription factors Fos (AP-1), Yan and Pnt in PCP dependent R3/R4 specification. Loss and gain-of-function assays suggest that the transcription factors integrate input from Fz/PCP and Egfr-signaling and that the ETS factors Pnt and Yan cooperate with Fos (and Jun) in the PCP-specific R3/R4 determination. The data indicate that Fos (either downstream of Fz/PCP signaling or parallel to it) and Yan are required in R3 to specify its fate (Fos) or inhibit R4 fate (Yan) and that Egfr-signaling is required in R4 via Pnt for its fate specification. Taken together with previous work establishing a Notch-dependent Su(H) function in R4, it is concluded that Fos, Yan, Pnt, and Su(H) integrate Egfr, Fz, and Notch signaling input in R3 or R4 to establish cell fate and ommatidial polarity (Weber, 2008).
Previous studies established that Fz is required cell-autonomously for R3 fate induction. The current analyses of kay/fos LOF alleles indicate that Fos is also required cell-autonomously in R3 for its fate determination. When overexpressed, Fos also acts like Fz in R3/R4 photoreceptors at the time of PCP establishment, with the cell of the pair that has higher Fos levels adopting the R3 fate. Based on its requirement in R3 and genetic interactions, Fos could act as a nuclear effector of Fz/PCP signaling. This is supported by the observation that it is able to suppress sev-dsh induced PCP defects; the genetic data can however not rule out that Fos could act in parallel to Fz/Dsh-PCP signaling). The subtle differences observed between fz and kay/fos LOF requirements (in fz− R3/R4 mosaics the wild-type cell adopts the R3 fate often causing chirality inversions, while in kay/fos mosaic pairs with a mutant R3 the pair often adopts symmetrical R4/R4 appearance) is likely due either to the hypomorphic nature of the kay/fos alleles that had to be used in the analysis or potential redundancy with jun (Weber, 2008).
In addition to the positive Fos signaling input, R3 specification also requires the repressor function of Yan, with Yan inhibiting R4 fate in the R3 precursor. This is evident by the cellular requirement of Yan and highlighted by the increased defects in a kay/fos and yan double mutant scenario, where both aspects are partially impaired causing frequent R3/R4 fate decision defects. The dominant enhancement of kay2 by yan LOF suggests that keeping the R4 fate off in R3 precursors is as important as inducing the R3 fate (Weber, 2008).
Previous work has demonstrated that Fz/PCP signaling leads to Dl and neur upregulation in R3, activating Notch signaling in the neighboring R4 precursor. This study shows that Egfr-signaling is also specifically required for R4 fate determination. The ETS factors Yan and Pnt are nuclear effectors of Egfr-signaling in many contexts including photoreceptor induction, and the data indicate that they act also in R3/R4 determination. Egfr-signaling leads to an inactivation of Yan and an activation of Pnt through their phosphorylation by the Rl/Erk MAPK. As Yan represses the R4 fate it needs to get inactivated in the R4 precursor by Egfr-signaling and conversely Pnt is activated in R4. Together with the Notch-Su(H) activity this leads to R4 fate induction. Thus, for R3 determination Fz/PCP signaling and its nuclear effectors Fos (and Jun) are sufficient, along with Yan mediated repression of the R4 fate in R3 precursors. R4 fate determination, on the other hand, requires the joint activity of two pathways, Notch and Egfr-signaling and their nuclear effectors. A similar Egfr-Notch cooperation is observed in R7 induction and in cone cells (Weber, 2008).
These data support a complex interaction scenario between Fz/PCP, Notch, and Egfr-signaling in R3/R4 fate determination. Whereas the Notch-Su(H) activation in R4 depends on Fz/PCP signaling in the R3 precursor, the Fz/PCP and Egfr-signaling pathways require a fine balance. This is reflected by their genetic interactions, both at the level of the receptors fz and Egfr and their nuclear effectors Fos/Jun and the ETS factors Pnt and Yan, suggesting a cooperative involvement between the Fz/PCP and Egfr pathways (Weber, 2008).
The nuclear Egfr-signaling response is very likely mediated by Pnt in R4. Although this could not be addressed in pnt LOF clones due to the non-autonomous defects, which are caused by feedback loop requirements in which Pnt participates. The sufficiency experiments fully support a cell-autonomous requirement of Pnt in R4 to specify R4 fate, consistent with the Egfr requirement (Weber, 2008).
In summary, the behavior of the nuclear effectors of the respective signaling pathways involved in R3/R4 specification reflects the combinatorial nature of the signaling pathway input into the R3 and R4 fates (Weber, 2008).
Although in the embryo Fos and Jun need to act as heterodimeric partners in a non-redundant manner, in imaginal discs the scenario is more complicated. Whereas jun mutant clones display only mild phenotypes and do not affect proliferation/survival, strong kay/fos LOF alleles show severe defects, suggesting that kay/fos is the main AP-1 component acting in imaginal discs. This is supported by recent studies on the role of Fos in cell cycle regulation and proliferation (Hyun, 2006). Nevertheless, the double mutant combination of kay and jun revealed a requirement of both as no kay/fos, jun double mutant cells are recovered, suggesting a partially redundant function of kay/fos and jun in imaginal discs (Weber, 2008).
The specific role of the possible distinct heterodimers between the different Fos isoforms and Jun, or the different Fos isoforms themselves, could be very complex. This complexity is also evident in the fact that overexpression of a dominant-negative Fos protein form or a single wild-type isoform (transcript RA, according to Flybase) causes similar phenotypic defects (e.g. in the eye or in thorax closure). Future experiments will have to address which of the Fos isoforms is required in which context and if and how they interact with Jun (Weber, 2008).
The Berkeley Drosophila Genome Project (BDGP) has identified a large number of cDNA clones corresponding to CG15507 and kay. Further sequence analyses indicated a previously unknown complex splicing pattern in the kay locus. At least five different promoter elements direct expression of distinct mRNA species encoding several different Fos isoforms. All proteins differ in their N-terminal domain but share a C-terminus containing the leucine zipper domain. Thus, based on sequence analysis shroud corresponds to kayak. In agreement with this notion shroud and kayak mutant embryos display very similar cuticle phenotypes and show similar morphogenetic defects. This is further supported by complementation data. The previously described kayak null mutation kay1 removes the kay2b exon including the translational start site. The kay2 mutation is classified as hypomorphic but no nucleotide change has been found. Ectopic expression of the Kay2a isoform rescues the cuticle differentiation phenotype but not the lethality. The sroP54 mutation fails to complement the presumed kay1 null allele and shows reduced viability in trans to the hypomorphic kay2 mutation (about 8% of the expected numbers eclosed; 307 flies analyzed). When kay1 was analyzed in trans to different EMS-induced sro alleles only 60%-35% of the expected transheterozygous flies eclosed, however, full complementation was found in trans to the hypomorphic kay2 allele, which itself is not strictly lethal (Giesen, 2003).
Bases in 5' UTR - 768
Bases in 5' UTR - 1097
The sequences of Fra and Jra share structural features with their mammalian AP-1 counterparts. The sequence of Fra resembles that of mammalian Fos, and the sequence of Jra resembles that of mammalian Jun. For example, the Fos basic domain responsible for the enhanced DNA binding of Fos-Jun complexes is 79% conserved in Fra. The corresponding domain of Jun is 89% conserved in Jra. The Drosophila AP-1 proteins also contain a leucine repeat present in Fos and Jun, required for formation of the Jun homodimer and the Fos-Jun heterodimer. The Fra leucine repeat differs from that of Fos, however, in that a methoinine residue replaces the third leucine. Another structural feature in common between the fly and mammalian AP-1 proteins is the relative position of the basic motif and adjacent leucine repeat within the various protein molecules. As in Fos, these structural features are present in the middle of Fra, whereas they are at the C-terminus of Jra and Jun. The rest of the sequences are not conserved. Fra and Jra each recognize the AP-1 site (Perkins, 1990).
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