Coronins have maintained a high degree of conservation over the roughly 800 million years of eukaryotic evolution.^1,2 From its origins as a single gene in simpler eukaryotes, the mammalian Coronin gene family has expanded to include at least six members (see Chapter 4). Increasing evidence indicates that Coronins play critical roles as regulators of actin dependent processes such as cell motility and vesicle trafficking^3,4 (see Chapters 6-9). Considering the importance of these processes, it is not surprising that recent findings have implicated the involvement of Coronins in multiple diseases. This review primarily focuses on Coronin 1C (HGNC symbol: CORO1C, also known as Coronin 3) which is a transcriptionally dynamic gene that is up-regulated in multiple types of clinically aggressive cancer. In addition to reviewing the molecular signals and events that lead to Coronin 1C transcription, we summarize the results of several studies describing the possible functional roles of Coronin 1C in development as well as disease progression. Here, the main focus is on brain development and on the progression of melanoma and glioma. Finally, we will also review the role of other mammalian Coronin genes in clinically relevant processes such as neural regeneration and pathogenic bacterial infections (see Chapter 10).

Coronin 1C: A Transcriptionally Dynamic Coronin Gene

One member of the mammalian Coronin gene family that is frequently observed to be up- or down-regulated in DNA microarray experiments is Coronin 1C. These data strongly suggest that this gene is transcriptionally dynamic, a finding supported by the fact that Coronin 1C was discovered in the early ‘90s as a gene that is induced by serum stimulation in fibroblasts.⁵ In this early work, Coronin 1C was identified as mig-3 for mitogen induced gene 3 and was not pursued. In 2004, Coronin 1C was independently identified as a serum-induced gene as part of a systematic search for genes that reflected a ‘wound signature’ in fibroblasts.⁶ The authors reasoned that fibroblast wound healing and tumor metastasis likely share a common set of up-regulated genes that may have prognostic value for clinical outcomes. Indeed, the expression of the 512 genes identified as part of the ‘core serum response’ does have strong predictive value for patient survival across a variety of tumors. More recently, Coronin 1C was identified as a delayed primary response gene in PDGF-stimulated glioblastoma cells.⁷ Together, these studies demonstrate that Coronin 1C is up-regulated at the transcriptional level by extracellular stimuli such as serum and growth factors. However, since these stimuli activate a large number of signaling cascades, these studies do not reveal much about the specific molecular events that increase Coronin 1C transcription.

In addition to these studies, other experiments have identified Coronin 1C as a target of specific pathways utilizing the transcription factors c-Myc/Max and Slug/Snail/E47. The activity of c-Myc and its partner Max has been frequently associated with human malignancies by contributing to cellular transformation and evasion of apoptosis. Coronin 1C was identified in a genome wide screen for promoters that bound to c-Myc in Burkitt's lymphoma cells.⁸ While this finding is intriguing, it is worth noting that this screen yielded a large number of target genes (>900) and may reflect global transcriptional regulation by c-Myc. In a more specific screen, Coronin 1C was identified as one of twenty target genes that were up-regulated upon expression of the transcription factors Snail, Slug and E47 in epithelial cells.⁹ Each of these transcription factors has been associated with epithelial-to-mesenchymal transition (EMT) in epithelial cells and they are consistently over-expressed in carcinoma cell lines with invasive and metastatic properties. This result suggests that Coronin 1C may be a strong candidate as both a biomarker for invasive cancer and functionally important for disease progression.

Consistent with the transcriptional dynamism of Coronin 1C, many other studies have identified this gene as either up- or down-regulated under various conditions (Fig. 1 and Table 1) and here we will highlight several of these studies that relate to cancer progression. Endometrial carcinoma (EC) is an extremely common gynecological malignancy that comprises two different types of tumor with a more benign type I EC and the more clinically aggressive nonendometriod endometrial carcinoma (NEEC). Coronin 1C is up-regulated 2.3 fold in NEEC relative to type I EC.¹⁰ In another study, Coronin 1C was identified as part of a 99-gene hypoxia expression signature in head and neck squamous cell carcinomas (HNSCC).¹¹ Since hypoxia is a strong negative prognostic factor in many tumors including HNSCC, this also points to the involvement of Coronin 1C in disease progression in this malignancy.¹² Finally, Coronin 1C was identified as one of 79 genes up-regulated in androgen-insensitive prostate cancer cell lines relative to androgen-sensitive cell lines.¹³ Since androgen insensitivity is a hallmark of aggressive prostate cancer, this further reinforces the link between Coronin 1C expression and invasion and metastasis.¹⁴

Figure 1

Inputs into the Coronin 1C promoter. Schematic diagram of the known signaling inputs that affect Coronin 1C transcription.

Table 1

Conditions under which Coronin 1C is transcriptionally regulated.

Coronin 1C as a Marker of Melanoma Progression

Advanced melanoma is one of the most feared human cancers.^15,16 Although curable through surgery when diagnosed at early stage, melanoma is characterized by its therapeutic resistance and aggressive clinical behavior. A proclivity for early metastasis is a key clinical feature of melanoma and in perhaps no other malignancy is the ability to metastasize more closely correlated with clinical outcome.^17,18 On the molecular level, one of the signature genetic events of melanoma is activation of the Ras/Raf pathway, with the majority (90%) of human melanomas harboring activating mutations in either N-RAS or B-RAF.^19-21 Activation of either of these molecules induces persistent activation of the Erk mitogen-activated protein kinase (MAPK) cascade,²² suggesting that aberrant activation of the Erk pathway is a critical step in melanoma development. A major consequence of Erk activation is regulation of gene expression. However, the gene targets of this pathway important for oncogenesis in melanoma have only recently begun to be elucidated.²³ These gene expression experiments and those from other groups have shown that cytoskeletal regulatory genes are frequently up-regulated during metastasis,^24,25 highlighting the importance of cell migration in the etiology of metastatic cancer. Understanding how actin dynamics become mis-regulated during metastasis may allow the identification of new diagnostic markers that predict metastatic potential and provide candidate targets for clinical intervention.

Recent work has examined Coronin 1C protein levels in both normal human skin and human melanoma.²⁶ Immunohistochemical staining reveals that, in normal skin, Coronin 1C levels are relatively low (Fig. 2A). This starkly contrasts with severe dysplastic nevi (abnormal moles more likely to develop into melanomas) and metastases, where the staining of tumor cells is much stronger (Fig. 2A). In order to determine if Erk is responsible for Coronin 1C up-regulation, three B-RAF mutant melanoma cell lines with high phospho-Erk levels (WM2664, SKMel24 and SKMel28) were examined by quantitative real-time PCR.²³ All three contain high levels of Coronin 1C mRNA which are significantly reduced upon treatment with the Erk inhibitor U0126 (Fig. 2B). These data indicate that Coronin 1C is a potential marker for melanoma progression and that its expression is at least partly dependent on activation of the Erk pathway.

Figure 2

Coronin 1C in melanoma. A) Immunohistochemical staining of the indicated tissue samples for Coronin 1C. 5 μm sections from melanoma tumors were stained with a new Coronin 1C specific mAb (Roadcap and Bear, unpublished reagent) for 30min at 37°C (more...)

Coronin 1C Expression Is Regulated during Murine Brain Development

The dynamics of Coronin 1C (Coronin 3) expression have also been studied in both the development and diseased state of the brain. Studies of Coronin 1C in brain tumor cells revealed a similar story to that presented above for melanoma and are presented in the next section of this chapter. Coronin 1C expression was also high in all regions of the developing brain and this section discusses the developmental and cell specific expression patterns that are observed during further brain maturation.²⁷

The neocortex consists of different laminae that are formed sequentially during the first postnatal days with the inner laminae differentiating first.²⁸ Coronin 1C expression follows this inside-out gradient and deeper cortical layers are the first to show a decrease in the expression of Coronin 1C.

By the later stages of brain development, Coronin 1C is detected only in a small peripheral cortical layer. Finally, only weak basal levels of Coronin 1C remain detectable after terminal differentiation of the cortical neurons (Fig. 3A, P1 and P20 are shown). Similarly, the high levels of Coronin 1C in immature neurons of the cerebellum are decreased after formation of the granule cell layers (Fig. 3B). Some types of neurons, including hippocampal pyramidal CA1-CA3 and Purkinje cells, retain strong expression of Coronin 1C until early murine adulthood (Fig. 3C, left image, analyzed up to 80 days). These neurons harbor a high degree of synaptic plasticity, which enables them to undergo long-term potentiation and depression processes like learning and memory.^29-32 Inversely to the patterns of the grey matter, areas of the white matter increase the expression of Coronin 1C (Fig. 3C, right image, only P30 is shown) during the progress of myelination.^33,34 It has been suggested that these localization patterns place Coronin 1C in a position to play a role in diverse processes such as neuronal migration, differentiation, formation of neurites and the formation of lamellar protrusions and myelin sheaths of oligodendroglial cells.²⁷

Figure 3

Coronin 1C expression levels during maturation of the grey and white matter of murine brain. Localization of Coronin 1C (Coronin 3) in sections of postnatal neocortex (A) and cerebellar sections (B, one folium is shown) of stages P1 and P20 analyzed by (more...)

These tightly controlled expression patterns suggest that imbalances in the expression of Coronin 1C during brain development might lead to defects in brain morphology. This hypothesis is supported by the observation that another member of the Coronin protein family, Coronin 1A, exhibits reduced expression levels in Down syndrome brain.³⁵ It is noteworthy that other WD40-repeat containing proteins—Coronin proteins represent the cytoskeleton-related subfamily of WD40-repeat proteins (see Chapter 2)—also have been linked to human diseases with malformations of the nervous system, namely the lissencephaly,^36,37 Cockayne syndrome,³⁸ late-onset sensorineural deafness³⁹ and the alacrima-achalasia-adrenal insufficiency (triple-A-syndrome).^40,41

Coronin 1C Is Associated with the Malignant Phenotype of Human Diffuse Gliomas

In parallel to the work on Coronin 1C (Coronin 3) in melanoma progression, Coronin 1C's role in coordinating migration and invasion of tumor cells in the human brain has been investigated. Previously, Coronin 1C was reported to exert a role in regulation of F-actin turnover during cell migration and neurite outgrowth.^4,42 To address a possible role of Coronin 1C in brain tumor cells, its expression in normal human brain tissue and various entities of human brain tumors was determined.⁴³

In the normal adult human brain tissue, neurons in the cortex have little Coronin 1C, while the white matter do not show any significant expression. In brain tumors, the expression levels of Coronin 1C depend on the tumor type. Benign meningiomas (Fig. 4A, left image), pilocytic astrocytomas, high-grade anaplastic astrocytomas, oligodendrogliomas, oligoastrocytomas and glioblastomas all strongly express Coronin 1C. Low grade diffuse astrocytomas (Fig. 4A, right image), oligodendrogliomas and oligoastrocytomas show only weak staining of Coronin 1C in the tumor cells, while no expression of Coronin 1C is detectable in tumors of neuronal origin like the desmoplastic medulloblastoma and neuroblastoma. In mixed glial tumors, the astroglial portion of the tumor often expresses Coronin 1C at higher levels than the oligodendroglial component. Within an individual tumor, tumor cells adjacent to proliferating microvessels exhibit a stronger Coronin 1C staining than those adjacent to areas of necrosis (Fig. 4B). In addition, the tumor matrix contains a varying number of reactive astrocytes, activated and migrating astrocytic cells, which also highly express Coronin 1C. This also was the case for reactive astrocytes and microglial cells that had been triggered by circumscriptive nontumor lesions such as infarcts and traumatic lesions (Fig. 4C, left image). In contrast, reactive astrocytes in epilepsia-related diffuse astrogliosis less strongly express Coronin 1C.

Figure 4

Coronin 1C expression levels are associated with the malignant phenotype of human gliomas. Paraffin-embedded tissue sections of human brain tumors were immunostained with a monoclonal antibody directed against Coronin 1C (Coronin 3), followed by biotinylated (more...)

A finding of significance is that Coronin 1C was associated with the malignant phenotype of diffuse gliomas.⁴³ This class of tumors includes astrocytomas, oligodendrogliomas and oligoastrocytomas. Diffuse gliomas clearly have a strong correlation between high Coronin 1C expression levels and increased grade of the malignancy (Fig. 4C, right image). Coronin 1C's demonstrated role in actin dynamics and cell motility suggests that its expression in astroglial cells and in glial tumor cells is related to migration and the malignant phenotype. This hypothesis was tested by shRNA-mediated knockdown of Coronin 1C in U373 and A172 glioblastoma cells.⁴³ Silencing Coronin 1C expression significantly reduces cell proliferation rates, cell migration velocity, formation of invadopodia, secretion of matrix metalloproteinases and invasion into extracellular matrix (Fig. 5A-C and data not shown). Previously, the degree of migration and invasion of tumor cells into healthy tissue was found to be a critical parameter of malignancy in diffuse gliomas and, moreover, a factor that limits the success of surgery.⁴⁴ Thus, these data provide strong evidence that the expression level of Coronin 1C correlates with the grade of malignancy of diffuse gliomas and that Coronin 1C is significantly involved in tumor cell proliferation, migration, invasion, malignant progression and possibly prognosis of diffuse gliomas.

Figure 5

Coronin 1C influences malignancy-related cellular functions. A) Proliferation rates of U373 and A172 glioblastoma cells lacking Coronin 1C (Coronin 3) expression (kd) are compared to control cells (ctrl); a certain number of cells was seeded and counted (more...)

Other Coronin Genes and Disease

Coronin 1A (Coronin 1) is highly expressed in the hematopoetic system and regulates F-actin content in thymocytes (discussed below).⁴⁵ Gene expression array studies suggest that its expression may be altered in lymphomas and other tumors of hematopeotic origin, although there is no apparent trend between cancer progression and Coronin 1A expression.^46-50 Since control of actin dynamics is an integral part many disease states, it follows that Coronins could play a role in diseases other than cancer. The best-characterized example of this is Coronin 1A's role in pathogenic bacterial infection.⁵¹ The standard immune response to bacterial infection involves macrophages engulfing bacteria via phagocytosis. By utilizing controlled membrane fusion of phagosomes with lysosomes, the macrophages are able to deliver lytic enzymes, acidify phagolysosomes and subsequently destroy the bacteria.⁵² Nucleation of actin filaments around nascent phagosomes plays an important role in mediating these critical vesicle fusion events and thus the immune response to bacterial infection can be considered an actin-dependent process.⁵³ Pathogenic bacteria such as Mycobacterium tuberculosis can circumvent the response by retaining Coronin 1A (called TACO in the original study) on the phagosome surface, thereby preventing the maturation of the phagosomes and allowing bacterial propagation within the macrophage.⁵¹ The mechanism of retention of Coronin 1A on bacterial-containing phagosomes was unclear for many years. A recent study, however, has identified the bacterial protein lipoamide dehydrogenase C (LpdC) as a Coronin 1A binding protein that recruits and retains Coronin 1A on the phagosome.⁵⁴ In this work, the authors demonstrated that enforced expression of LpdC increased the survival of normally nonpathogenic bacteria in macrophages. Together, these data are highly suggestive that pathogenic bacteria are hijacking Coronin 1A function to alter actin dynamics on macrophage phagosomes and thereby evading the normal immune response.

Alternately, evidence also exists that Coronin 1A's role may be to control calcium dynamics after bacterial infection.⁵⁵ Macrophages from mice lacking Coronin 1A do not display the persistent increase in calcium levels that are normally displayed after infection. This consequently prevents the activation of signaling pathways via proteins such as the calcium-sensitive phosphatase Calcineurin. While no alterations in actin dependent processes have been detected in Coronin 1A null macrophages, the effects may be linked to more subtle effects on actin that affect the known relationship between cytoskeletal dynamics and calcium trafficking.^56,57 Dramatic effects on actin-dependent processes may also be masked by the presence of functionally redundant Coronin isoforms in this cell type.

While Coronin 1A is utilized to the detriment of macrophages after pathogenic bacterial infection, it plays a large role in the normal immune system as the most prominent hematopoietic Coronin.⁴⁵ For instance, T-cells from Coronin 1A null mice are profoundly defective in both their ability to undergo chemotaxis in vitro and to home to secondary lymphocyte organs in vivo. Together, these defects lead to a decrease in the levels of CD4⁺ and CD8⁺ T-cells in the blood, spleen and lymph nodes of Coronin 1A deficient mice. This phenotype was linked to Coronin 1A's ability to control steady-state F-actin levels via regulation of Arp2/3. Loss of Coronin 1A could therefore lead to an increased rate of immune system failure and a consequent susceptibility to numerous diseases, although this hypothesis has yet to be tested. Further information on Coronin proteins in lymphocytes and macrophages can be found in Chapters 8 6th section and 10.

Coronin 1B (Coronin 2) is the most ubiquitously expressed mammalian isoform of Coronin, but relatively few studies have examined its role in disease states.⁵⁸ It has, however, been linked to neurite formation and axon regeneration following spinal cord injury.⁵⁹ p53 activation following injury stimulates the formation and growth of neurites that facilitate regeneration of neural pathways and knockdown of Coronin 1B decreases this neurite outgrowth.⁶⁰ Coronin 1B activity therefore, like that of Coronin 1C, may be linked to neurodegenerative diseases or even control of neuronal plasticity. Further study of Coronin 1B is necessary to facilitate understanding of its role in diseases, but there is strong evidence that it plays an important role in regulating actin dynamics at the leading edge of motile cells.³ Disruption of this process may be important for a number of motility-involving diseases.

Unanswered Questions and Future Directions

Although Coronins (and particularly Coronin 1C (Coronin 3)) have been implicated in disease states, much work remains to establish functional links between transcriptional regulation and phenotypic change. One important area that will require more work is the careful delineation of the Coronin 1C promoter and its immediate upstream inputs. In addition, the biochemical mechanism of Coronin 1C activity needs to be more precisely determined and the relevant binding partners necessary for this activity need to be identified. Understanding these issues may be important for revealing how diverse signaling cascades are dis-regulated in invasive/metastatic cancer. Another area that will require future studies is clarifying the role that Coronin proteins play in development. Continued analysis of mouse gene deletion models should be quite informative in this regard.

Acknowledgements

We would like to thank Dan Zedek, Nancy Thomas and Nick Holoweckyj for contributions to Figure 2. DR is supported by NIH (NRSA, F32 CA128297), CSC is supported by the DFG (NO 113/13-3) and Köln Fortune, JEB is supported by the Melanoma Research Foundation and the Sontag Foundation.

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These authors contributed equally to this work.