Fictionalising Trauma : The Aesthetics of Marguerite Duras's India Cycle

Marguerite Duras (1914−1996) was one of the most original French writers and film directors, whose cycles are renowned for a transgeneric repetition variation of human suffering in the modern condition. Her fictionalisation of Asian colonialism, the India Cycle (1964−1976), consists of three novels, Le ravissement de Lol V. Stein (1964), Le Vice-consul (1966) and L'amour (1971), a theatre play, India Song (1973), and three films, La Femme du Gange (1973), India Song (1974) and Son nom de Venise dans Calcutta desért (1976). Duras’s cultural position as a colon in inter-war ‘Indochina’ was the backdrop for this “théâtre-text-film”, while its creation was provoked by the atrocities of World War II and post-war decolonisation. Fictionalising Trauma analyses the aesthetics of the India Cycle as Duras’s critical working-through of historical trauma. From an emotion-focused cognitive viewpoint, the study sheds light on trauma’s narrativisation using the renewed concept of traumatic memory developed by current social neuroscience. Duras is shown to integrate embodied memory and narrative memory into an emotionally progressing fiction. Thus the rhetoric of the India Cycle epitomises a creative symbolisation of the unsayable, which revises the concept of trauma from a semiotic failure into an imaginative metaphorical process. The India Cycle portrays the stagnated situation of a white society in Europe and British India during the thirties. The narratives of three European protagonists and one fictional Cambodian mendicant are organised as analogues mirroring the effects of rejection and loss on both sides of the colonial system. Using trauma as a conceptual prism, the study rearticulates this composition as three roles: those of witnessing writers, rejected survivors and colonial perpetrators. Three problems are analysed in turn by reading the non-verbal markers of the text: the white man as a witness, the subversive trope of the madwoman and the deadlock of the colonists’ destructive passion. The study reveals emotion and fantasy to be crucial elements in critical trauma fiction. Two devices intertwine throughout the cycle: affective images of trauma expressing the horror of life and death, and self-reflexive metafiction distancing the face-value of the melodramatic stories. This strategy dismantles racist and sexist discourses underpinning European life, thus demanding a renewal of cultural memory by an empathic listening to the ‘other’. And as solipsism and madness lead the lives of the white protagonists to tragic ends, the ‘real’ beggar in Calcutta lives in ecological harmony with Nature. This emphasises the failure of colonialism, as the Durasian phantasm ambiguously strives for a deconstruction of the exotic mythical fiction of French ‘Indochina’.

Structure informationnelle et constructions du kabyle : Etude de trois types de phrase dans le cadre de la grammaire constructionnelle

Information structure and Kabyle constructions Three sentence types in the Construction Grammar framework The study examines three Kabyle sentence types and their variants. These sentence types have been chosen because they code the same state of affairs but have different syntactic structures. The sentence types are Dislocated sentence, Cleft sentence, and Canonical sentence. I argue first that a proper description of these sentence types should include information structure and, second, that a description which takes into account information structure is possible in the Construction Grammar framework. The study thus constitutes a testing ground for Construction Grammar for its applicability to a less known language. It constitutes a testing ground notably because the differentiation between the three types of sentences cannot be done without information structure categories and, consequently, these categories must be integrated also in the grammatical description. The information structure analysis is based on the model outlined by Knud Lambrecht. In that model, information structure is considered as a component of sentence grammar that assures the pragmatically correct sentence forms. The work starts by an examination of the three sentence types and the analyses that have been done in André Martinet s functional grammar framework. This introduces the sentence types chosen as the object of study and discusses the difficulties related to their analysis. After a presentation of the state of the art, including earlier and more recent models, the principles and notions of Construction Grammar and of Lambrecht s model are introduced and explicated. The information structure analysis is presented in three chapters, each treating one of the three sentence types. The analyses are based on spoken language data and elicitation. Prosody is included in the study when a syntactic structure seems to code two different focus structures. In such cases, it is pertinent to investigate whether these are coded by prosody. The final chapter presents the constructions that have been established and the problems encountered in analysing them. It also discusses the impact of the study on the theories used and on the theory of syntax in general.

La contextualisation du discours radiophonique par des moyens prosodiques. L’exemple de cinq grands philosophes français du XXe siècle

"Radiodiskurssin kontekstualisointi prosodisin keinoin. Esimerkkinä viisi suurta ranskalaista 1900-luvun filosofia" Väitöskirja käsittelee puheen kontekstualisointia prosodisin keinoin. Toisin sanottuna työssä käsitellään sitä, miten puheen prosodiset piirteet (kuten sävelkulku, intensiteetti, tauot, kesto ja rytmi) ohjaavat puheen tulkintaa vanhastaan enemmän tutkittujen sana- ja lausemerkitysten ohella. Työssä keskitytään seitsemään prosodisesti merkittyyn kuvioon, jotka koostuvat yhden tai usean parametrin silmiinpistävistä muutoksista. Ilmiöitä käsitellään sekä niiden akustisten muotojen että tyypillisten esiintymisyhteyksien ja diskursiivisten tehtävien näkökulmasta. Aineisto koostuu radio-ohjelmista, joissa puhuu viisi suurta ranskalaista 1900-luvun filosofia: Gaston Bachelard, Albert Camus, Michel Foucault, Maurice Merleau-Ponty ja Jean-Paul Sartre. Ohjelmat on lähetetty eri radiokanavilla Ranskassa vuosina 1948–1973. Väitöskirjan tulokset osoittavat, että prosodisesti merkityt kuviot ovat moniulotteisia puheen ilmiöitä, joilla on keskeinen rooli sanotun kontekstualisoinnissa: ne voivat esimerkiksi nostaa tai laskea sanotun informaatioarvoa, ilmaista puhujan voimakasta tai heikkoa sitoutumista sanomaansa, ilmaista rakenteellisen kokonaisuuden jatkumista tai päättymistä, jne. Väitöskirja sisältää myös kontrastiivisia osia, joissa ilmiöitä verrataan erääseen klassisessa pianomusiikissa esiintyvään melodiseen kuvioon sekä erääseen suomen kielen prosodiseen ilmiöön. Tulokset viittaavat siihen, että tietynlaista melodista kuviota käytetään samankaltaisena jäsentämiskeinona sekä puheessa että klassisessa musiikissa. Lisäksi tulokset antavat viitteitä siitä, että tiettyjä melodisia muotoja käytetään samankaltaisten implikaatioiden luomiseen kahdessa niinkin erilaisessa kielessä kuin suomessa ja ranskassa. Yksi väitöskirjan osa käsittelee pisteen ja pilkun prosodista merkitsemistä puheessa. Tulosten mukaan pisteellä ja pilkulla on kummallakin oma suullinen prototyyppinsä: piste merkitään tyypillisesti sävelkulun laskulla ja tauolla, ja pilkku puolestaan sävelkulun nousulla ja tauolla. Merkittävimmät tulokset koskevat kuitenkin tapauksia, joissa välimerkki tulkitaan prosodisesti epätyypillisellä tavalla: sekä pisteellä että pilkulla vaikuttaisi olevan useita eri suullisia vastaavuuksia, ja välimerkkien tehtävät voivat muotoutua hyvin erilaisiksi niiden prosodisesta tulkinnasta riippuen.

Pour une éthique du traducteur poéticien

This doctoral thesis starts with a comprehensive introduction seeking to anchor the problematics of the ethics of the poetician translator (a translator of literary and similar texts) in a theoretical framework drawing on moral philosophy. This introductory section is followed by six published papers (four journal articles and two papers from conference proceedings), forming the main body of the thesis, which progressively develop a possible application of this theoretical framework. Starting from the acknowledgement that one of the ethical stakes in translation is constructed around the relation to the foreign and to the other , the translation process is scrutinized through the prism of the philosophies of Dialogue , focusing on how the translating actors relate to their task. The central notions around which philosophies of Dialogue are built are introduced and applied to translation. The question of intersubjective relations, addressed from a philosophical perspective, is developed with the help of the works of Martin Buber, Gabriel Marcel, Emmanuel Levinas and Paul Ric ur. The introductory section presents and explicates the thought of each of these philosophers and extracts the concepts that are then developed in the articles and conference papers collected here. Each paper concentrates on the notions of one of the philosophers referred to above and places these notions in perspective with other philosophies of Dialogue. All the papers contribute to explicating the relationship between the multiple philosophical notions that address the problematics of alterity and the condition of the translator. The work as a whole leads to the idea that the task of the poetician translator is not only to translate a text properly but above all to rouse and increase the desire of linguistic communities to live together.

Les noms mythologiques du Banquet de Platon en traduction

Tutkielman aihe on mytologisten nimien kääntäminen Platonin Pitojen kuudessa käännöksessä (ranska, englanti, saksa, suomi, ruotsi, viro). Lähtökohtana oli selvittää, mikä käännösstrategia heijastaa selkeimmin Platonin periaatetta, jonka mukaan etymologia kuvaa nimen tarkoitteen luonnetta. Käännöksiä tarkastellaan kontrastiivisen analyysin keinoin. Käännösten mytologisia nimiä sisältäviä otteita analysoidaan ja vertaillaan sekä keskenään että alkutekstin kanssa. Tarkoituksena on selvittää, miten ja missä nimien merkitys välittyy käännösten lukijoille. Tutkielmassa käsitellään myös nimiin liittyviä käännösongelmia sekä syitä erilaisiin strategiavalintoihin. Tähän pyritään esittelemällä kääntäjien ja asiantuntijoiden näkemyksiä nimien kääntämisestä. Tiedot perustuvat sähköpostitse ja suullisesti tehtyihin haastatteluihin. Aiheen valinta johtuu siitä, että haluttiin osoittaa, miten paljon mytologisten nimien kääntäminen tai kääntämättä jättäminen voi vaikuttaa käännösten ymmärrettävyyteen ja helppolukuisuuteen. Kääntäjät ja asiantuntijat eivät kuitenkaan usein tiedosta tätä ongelmaa vaan lähestyvät nimiä pääasiassa kahdella vastakkaisella tavalla, joko kääntämällä ta transkriboimalla. Heidän näkemyksensä asiasta ovat hyvin erilaisia ja ristiriitaisia, eikä kompromissia ei ole syntynyt. Teoreettinen viitekehys on käännösteoreettinen. Ensin määritellään käännösstrategiat, joita nimien kääntämisessä käytetään - yleensä ja tutkituissa käännöksissä. Käsitteiden jaottelun peruslähtökohtana on se, missä määrin strategia paljastaa käännösyksikön merkityksen. Käännösanalyysin tueksi esittellään antiikin etymologian ja personifikaation käyttöä. Käännösosuudessa analysoidaan käännöksiä ja niitä verrataan alkuteksteihin. Kontrastiivisen analyysin avulla osoitetaan, että Pitojen mytologiset nimet eivät ole erisnimiä ja selvitetään, missä määrin niitä käsitellään käännöksissä yleis- ja missä määrin erisniminä. Käännösanalyysissä tutkitaan käännösratkaisuja ja nimien ja niihin perustuvien sanaleikkien merkityksen välittymistä juoksevassa tekstissä. Perusoletus oli se, että nimien kääntäminen on ongelmallista. Haluttiin selvittää, missä määrin niiden sisältämä informaatio välittyy lukijalle käännöksissä. Analyysi osoittaa, että kääntäminen välittää tehokkaimmin nimien merkityksen. Se on kuitenkin vaikeaa, koska nimillä ei ole vastineita, jotka kattaisivat niiden semanttiset, filosofiset ja kulttuuriset konnotaatiot. Nimet tuottavat ongelmia myös informaatiotiheyden kannalta. Jos ne käännetään, osa konnotaatioista jää välittämättä. Jos ne transkriboidaan, ne jäävät opaakeiksi. Tekstin koherenssi rikkoutuu, jos samat nimet milloin transkriboidaan, milloin käännetään. Jos nimien johdoksiin perustuvat sanaleikit käännetään mutta mytologiset nimet transkriboidaan, yhteys katoaa. Lopuksi tarkastellaan strategianvalinnan syitä, joita ovat nykyaikaistetun lähtötekstin vaikutus, eri käännöstraditiot, kääntäjien mieltymykset, filosofiset teoriat sekä kohdeyleisö. Kääntäjän on mietittävä, mikä on lukijalle tarkoituksenmukaista. Analyysin mukaan transkriboidut nimet ovat usein opaakkeja ja tekevät tekstistä vaikeaselkoisen. Analyysin selkein tulos lienee se, että nimien merkityksen eksplisitointi juoksevassa tekstissä ilmentää parhaiten niiden tärkeää etymologiaa. Tämä havainto voisi ehkä saada kääntäjät ja asiantuntijat pohtimaan ratkaisujaan ja johtaa kompromisseihin, joissa merkitys ja muut aspektit yritettäisiin välittää yhdessä. Tutkimus voi lisäksi valaista Platonin etymologian käyttöä sekä personifikaatiota, jota on tutkittu vähän. Avainsanat: Platon, Pidot, Erisnimet, Kääntäminen, Etymologia, Kontrastiivinen analyysi

Nés sous de bons auspices? Etude qualitative de facteurs contribuant à l'acquisition du bilinguisme par les enfants d'un couple mixte

Pro gradu- tutkielmassani tarkastelen suomi-ranska kaksikielisyyden kehittymistä perheissä, joissa vanhemmilla on eri äidinkieli. Työni tavoitteena on ollut tutkia kuinka eri ympäristötekijät vaikuttavat kaksikielisyyden omaksumiseen ja miten perheiden erilainen panostus vähemmistökielen, ts. kielen joka ei esiinny ympäristössä, oppimiseen näkyy saavutetuissa tuloksissa. Tutkimukseeni osallistui 13 perhettä, joilla on 10-12 vuotiaita, ranskaa ja suomea päivittäin käyttäviä lapsia. Lapsia oli yhteensä 18. Voidakseni tarkastella myös kieliympäristön vaikutusta oppimiseen valittiin perheistä kuusi Suomesta ja seitsemän Ranskasta sekä Sveitsin ranskankieliseltä alueelta. Tutkimusmenetelmiini kuului vanhempien haastattelu perheen sosiolingvististen tekijöiden selville saamiseksi ja lasten kanssa keskustelu suullisen kielitaidon arvioimiseksi. Pääpaino kielitaidon arvioinnissa oli kuitenkin kirjallisella tekstillä, jonka lapset tuottivat molemmilla kielillä tekstittömän kirjan kuvien perusteella. Teksteistä suoritettiin virheanalyysit, joissa eri virheet jaettiin ortografisiin, semanttisiin ja kieliopillisiin virheisiin. Jokaiselle lapselle lasketiin myös keskiarvo, joka osoitti kuinka monta sanaa tekstissä oli jokaista virhettä kohti. Näiden keskiarvojen pohjalta tutkittiin yhteneväisyyksiä virhemäärien sekä perheiden sosiolingvististen tekijöiden kesken. Yhteenvedossa verrattiin myös tuloksia teoriaosassa esitettyihin kielitieteilijöiden tarjoamiin periaatteisiin. Tutkielman perusteella voidaan todeta, että ympäristön vaikutus näytetään usein aliarvioitaneen kaksikielisyyttä koskevissa teoksissa. Hyvään kielitaitoon vähemmistökielessä tarvitaan enemmän kuin yksi kieli - yksi henkilö menetelmä, jossa vanhemmat puhuvat lapselle omaa äidinkieltään. Hyviksi vahvistuskeinoiksi havaittiin varsinkin kaksikielinen koulu sekä useat vierailut toisen vanhemman kotimaahan. Varsinkin perheen nuorimpien lasten vähemmistökielen oppimiseen tulisi panostaa sillä näillä on syntymästään asti mahdollisuus käyttää enemmistökieltä myös vanhempien sisarusten kanssa. Kieliympäristön vaikutuksesta havaittiin, että Suomessa asuvat lapset hallitsivat yleisesti ottaen paremmin vähemmistökielensä kuin Ranskassa asuvat. Tähän pidettiin syynä ranskalais-suomalaisen koulun positiivista vaikutusta kielen oppimiselle sekä ranskankielen arvostettua asemaa Suomessa. Avainsanat: Kaksikielisyys, kieltenoppiminen, bilinguisme, acquisition des langues, couple mixte

Le naturalisme finlandais : Une conception entropique du quotidien

Le naturalisme finlandais. Une conception entropique du quotidien. Finnish Naturalism. An Entropic Conception of Everyday Life. Nineteenth century naturalism was a strikingly international literary movement. After emerging in France in the 1870s, it spread all over Europe including young, small nations with a relatively recent literary tradition, such as Finland. This thesis surveys the role and influence of French naturalism on the Finnish literature of the 1880s and 1890s. On the basis of a selection of works of six Finnish authors (Juhani Aho, Minna Canth, Kauppis-Heikki, Teuvo Pakkala, Ina Lange and Karl August Tavaststjerna), the study establishes a view of the main features of Finnish naturalism in comparison with that of French authors, such as Zola, Maupassant and Flaubert. The study s methodological framework is genre theory: even though naturalist writers insisted on a transparent description of reality, naturalist texts are firmly rooted in general generic categories with definable relations and constants on which European novels impose variations. By means of two key concepts, entropy and everyday life , this thesis establishes the parameters of the naturalist genre. At the heart of the naturalist novel is a movement in the direction of disintegration and confusion, from order to disorder, from illusion to disillusion. This entropic vision is merged into the representation of everyday life, focusing on socially mediocre characters and discovering their miseries in all their banality and daily grayness. By using Mikhail Bakhtin s idea of literary genres as a means of understanding experience, this thesis suggests that everyday life is an ideological core of naturalist literature that determines not only its thematic but also generic distinctions: with relation to other genres, such as to Balzac s realism, naturalism appears primarily to be a banalization of everyday life. In idyllic genres, everyday life can be represented by means of sublimation, but a naturalist novel establishes a distressing, negative everyday life and thus strives to take a critical view of the modern society. Beside the central themes, the study surveys the generic blends in naturalism. The thesis analyzes how the coalition of naturalism and the melodramatic mode in the work of Minna Canth serves naturalisms ambition to discover the unconscious instincts underlying daily realities, and how the symbolic mode in the work of Juhani Aho duplicates the semantic level of the apparently insignificant, everyday naturalist details. The study compares the naturalist novel to the ideological novel (roman à these) and surveys the central dilemma of naturalism, the confrontation between the optimistic belief in social reform and the pessimistic theory of determinism. The thesis proposes that the naturalist novel s contribution to social reform lies in its shock effect. By means of representing the unpleasant truth the entropy of everyday life it aims to scandalize the reader and make him aware of the harsh realities that might apply also to him.

The Neurofibromatosis 2 tumor suppressor merlin in cytoskeleton organization and cell cycle regulation

Neurofibromatosis 2 (NF2) is a dominantly inherited disorder, which predisposes to multiple tumours of the nervous system, typically schwannomas and meningiomas. Biallelic inactivation of the NF2 gene occurs both in sporadic and NF2-related schwannomas and in most meningiomas. The NF2 gene product merlin (or schwannomin) is structurally related to the ERM proteins, ezrin, radixin and moesin, which act as molecular linkers between the actin cytoskeleton and the plasma membrane. Merlin is a tumor suppressor that participates in cell cycle regulation. Merlin s phosphorylation status appears to be associated with its tumour suppressor activity, i.e. non-phosphorylated merlin functions as a tumour suppressor, whereas protein phosphorylation results in loss of functional activity. This thesis study was initiated to investigate merlin s role as a tumor suppressor and growth inhibitor. These studies show, that like many other tumor suppressors, also merlin is targeted to the nucleus at some stages of the cell cycle. Merlin s nuclear localization is regulated by cell cycle phase, contact inhibition and adhesion. In addition, a potential nuclear binding partner for merlin was identified, Human Enhancer of Invasion 10 (HEI10), a cyclin B interacting protein. Many tumor suppressors interact with microtubules and this thesis work shows that also merlin colocalizes with microtubules in mitotic structures. Merlin binds microtubules directly, and increases their polymerization in vitro and in vivo. In addition, primary mouse Schwann cells lacking merlin displays disturbed microtubule cytoskeleton. Fourth part of this thesis work began from the notion that PKA phosphorylates an unidentified site from the merlin N-terminus. Our studies show that serine 10 is a target for PKA and modulation of this residue regulates cytoskeletal organization, lamellipodia formation and cell migration. In summary, this thesis work shows that merlin s role is much more versatile than previously thought. It has a yet unidentified role in the nucleus and it participates in the regulation of both microtubules and the actin cytoskeleton. These studies have led to a better understanding of this enigmatic tumor suppressor, which eventually will aid in the design of specific drugs for the NF2 disease.

Defects in tricarboxylic acid cycle enzymes Fumarate hydratase and Succinate dehydrogenase in cancer

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a recently characterized cancer syndrome which predisposes to cutaneous and uterine leiomyomas as well as renal cell carcinoma (RCC). Uterine leiomyosarcoma (ULMS) has also been observed in certain Finnish HLRCC families. The predisposing gene for this syndrome, fumarate hydratase (FH), was identified in 2002. The well-known function of FH is in the tricarboxylic acid cycle (TCAC) in the energy metabolism of cells. As FH is a novel cancer gene, the role of FH mutations in tumours is in general unknown. Similarly, the mechanisms through which defective FH is associated with tumourigenesis are unclear. The loss of a wild type allele has been observed in virtually all HLRCC patients tumours and the FH enzyme activities are either totally lost or remarkably reduced in the tissues of mutation carrier patients. Therefore, FH is assumed to function as a tumour suppressor. Mutations in genes encoding subunits of other TCAC enzyme SDH have also been reported recently in tumours: mutations in SDHB, SDHC, and SDHD genes predispose to paraganglioma and pheochromocytoma. In the present study, mutations in the SDHB gene were observed to predispose to RCC. This was the first time that mutations in SDHB have been detected in extra-paraganglial tumours. Two different SDHB mutations were observed in two unrelated families. In the first family, the index patient was diagnosed with RCC at the age of 24 years. Additionally, his mother with a paraganglioma (PGL) of the heart and his maternal uncle with lung cancer were both carriers of the mutation. The RCC of the index patient and the PGL of his mother showed LOH. In the other family, an SDHB mutation was detected in two siblings who were both diagnosed with RCC at the ages of 24 and 26 years. Both of the siblings also suffered PGL. All these tumours showed LOH. Therefore, we concluded that mutations in SDHB predispose also for RCC in certain families. Several tumour types were analysed for FH mutations to define the role of FH mutations in these tumour types. In addition, patients with a putative cancer phenotype were analysed to identify new HLRCC families. Three FH variants were detected, of which two were novel. One of the variants was observed in a patient diagnosed with ULMS at the age of 41 years. However, LOH was not detected in the tumour tissue. The FH enzyme activity of the mutated protein was clearly reduced, being 43% of the activity of the normal protein. Together with the results from an earlier study we calculated that the prevalence of FH mutations in Finnish non-syndromic ULMS is around 2.4%. Therefore, FH mutations seem to have a minor role in the pathogenesis on non-syndromic ULMS. Two other germline variants were detected in a novel tumour type, ovarian mucinous cystadenoma. However, tumour tissues of the patients were not available for LOH studies and therefore LOH status remained unclear. Therefore, it is possible that FH mutations predispose also for ovarian tumours but further studies are needed to verify this result. A novel variant form of the FH gene (FHv) was identified and characterized in more detail. FHv contains an alternative first exon (1b), which appeared to function as 5 UTR sequence. The translation of FHv is initiated in vitro from exons two and three. The localization of FHv is both cytosolic and nuclear, in contrast to the localization of FH in mitochondria. FHv is expressed at low levels in all human tissues. Interestingly, the expression was induced after heat shock treatment and in chronic hypoxia. Therefore, FHv might have a role e.g. in the adaptation to unfavourable growth conditions. However, this remains to be elucidated.

Molecular and clinical characteristics of tricarboxylic acid cycle-associated tumors

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare, dominantly inherited tumor predisposition syndrome characterized by benign cutaneous and uterine (ULM) leiomyomas, and sometimes renal cell cancer (RCC). A few cases of uterine leiomyosarcoma (ULMS) have also been reported. Mutations in a nuclear gene encoding fumarate hydratase (FH), an enzyme of the mitochondrial tricarboxylic acid cycle (TCA cycle), underlie HLRCC. As a recessive condition, germline mutations in FH predispose to a neurological defect, FH deficiency (FHD). Hereditary paragangliomatosis (HPGL) is a dominant disorder associated with paragangliomas and pheochromocytomas. Inherited mutations in three genes encoding subunits of succinate dehydrogenase (SDH), also a TCA cycle enzyme, predispose to HPGL. Both FH and SDH seem to act as tumor suppressors. One of the consequences of the TCA cycle defect is abnormal activation of HIF1 pathway ( pseudohypoxia ) in the HLRCC and HPGL tumors. HIF1 drives transcription of genes encoding e.g. angiogenetic factors which can facilitate tumor growth. Recently hypoxia/HIF1 has been suggested to be one of the causes of genetic instability as well. One of the aims of this study was to broaden the clinical definers of HLRCC. To determine the cancer risk and to identify possible novel tumor types associated with FH mutations eight Finnish HLRCC/FHD families were extensively evaluated. The extension of the pedigrees and the Finnish Cancer Registry based tumor search yielded genealogical and cancer data of altogether 868 individuals. The standardized incidence ratio-based comparison of HLRCC/FHD family members with general Finnish population revealed 6.5-fold risk for RCC. Moreover, risk for ULMS was highly increased. However, according to the recent and more stringent diagnosis criteria of ULMS many of the HLRCC uterine tumors previously considered malignant are at present diagnosed as atypical or proliferative ULMs (with a low risk of recurrence). Thus, the formation of ULMS (as presently defined) in HLRCC appears to be uncommon. Though increased incidence was not observed, interestingly the genetic analyses suggested possible association of breast and bladder cancer with loss of FH. Moreover, cancer cases were exceptionally detected in an FHD family. Another clinical finding was the conventional (clear cell) type RCC of a young Spanish HLRCC patient. Conventional RCC is distinct from the types previously observed in this syndrome but according to these results, FH mutation may underlie some of young conventional cancer cases. Secondly, the molecular pathway from defective TCA cycle to tumor formation was intended to clarify. Since HLRCC and HPGL tumors display abnormally activated HIF1, the hypothesis on the link between HIF1/hypoxia and genetic instability was of interest to study in HLRCC and HPGL tumor material. HIF1α (a subunit of HIF1) stabilization was confirmed in the majority of the specimens. However, no repression of MSH2, a protein of DNA mismatch repair system, or microsatellite instability (MSI), an indicator of genetic instability, was observed. Accordingly, increased instability seems not to play a role in the tumorigenesis of pseudohypoxic TCA cycle-deficient tumors. Additionally, to study the putative alternative functions of FH, a recently identified alternative FH transcript (FHv) was characterized. FHv was found to contain instead of exon 1, an alternative exon 1b. Differential subcellular distribution, lack of FH enzyme activity, low mRNA expression compared to FH, and induction by cellular stress suggest FHv to have a role distinct from FH, for example in apoptosis or survival. However, the physiological significance of FHv requires further elucidation.

Role of cell cycle regulators in development of the inner ear

The inner ear originates from an ectodermal thickening called the otic placode. The otic placode invaginates and closes to an otic vesicle, the otocyst. The otocyst epithelium undergoes morphogenetic changes and cell differentiation, leading to the formation of the labyrinth-like mature inner ear. Epithelial-mesenchymal interactions control inner ear morphogenesis, but the modes and molecules are largely unresolved. The expressions of negative cell cycle regulators in the epithelium of the early-developing inner ear have also not been elucidated. The mature inner ear comprises the hearing (cochlea) and balance (vestibular) organs that contain the nonsensory and sensory cells. In mammals, the inner ear sensory cells, called hair cells, exit the cell cycle during embryogenesis and are mitotically quiescent during late-embryonic differentiation stages and postnatally. The mechanisms that maintain this hair cell quiescense are largely unresolved. In this work I examined 1) the epithelial-mesenchymal interactions involved in inner ear morphogenesis, 2) expression of negative cell cycle regulators in the epithelium of the early developing inner ear and 3) the molecular mechanisms that maintain the postmitotic state of inner ear sensory cells. We observed that during otocyst stages, epithelial fibroblast growth factor 9 (Fgf9) communicates with the surrounding mesenchyme, where its receptors are expressed. Fgf9 inactivation leads to reduced proliferation of the surrounding vestibular mesenchyme and to the absence of semicircular canals. Semicircular canal development is blocked, since fusion plates do not form. These results show that the mesenchyme directs fusion plate formation and give direct evidence for the existence of reciprocal epithelial-mesenchymal interactions in the developing inner ear. Cyclin-dependent kinase inhibitors (CKIs) are negative regulators of proliferation. We show that the members of the Cip/Kip family of CKIs (p21Cip1, p27Kip1 and p57Kip2) are expressed in the early-developing inner ear. Our expression data suggest that CKIs divide the otic epithelium into proliferative and nonproliferative compartments that may underlie shaping of the otocyst. At later stages, CKIs regulate proliferation of the vestibular appendages, and this may regulate their continual growth. In addition to restricting proliferation, CKIs may play a role in regional differentiation of various epithelial cells. Differentiating and adult inner ear hair cells are postmitotic and do not proliferate in response to serum or mitogenic growth factors. In our study, we show that this is the result of the activity of negative cell cycle regulators. Based on expression profiles, we first focused on the retinoblastoma (Rb) gene, which functions downstream of the CKIs. Analysis of the inner ear phenotype of Rb mutant mice show, that the retinoblastoma protein regulates the postmitotic state of hair cells. Rb inactivation leads to hyperplasia of vestibular and cochlear sensory epithelia that is a result of abnormal cell cycle entry of differentiated hair cells and of delayed cell cycle exit of the hair cell precursor cells. In addition, we show that p21Cip1 and p19Ink4d cooperate in maintaining the postmitotic state of postnatal auditory hair cells. Whereas inactivation of p19Ink4d alone leads to low-level S-phase entry (Chen et al., 2003) and p21Cip1 null mutant mice have a normal inner ear phenotype, codeletion of p19Ink4d and p21Cip1 triggers high-level S-phase entry of auditory hair cells during early postnatal life, which leads to supernumerary hair cells. The ectopic hair cells undergo apoptosis in all of the mutant mice studied, DNA damage being the immediate cause of this death. These findings demonstrate that the maintenance of the postmitotic state of hair cells is regulated by Rb and several CKIs, and that these cell cycle regulators are critical for the lifelong survival of hair cells. These data have implications for the future design of therapies to induce hair cell regrowth.