Browsing by Subject "HOMOLOG"

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  • Laine, Anni; Nagelli, Srikar G.; Farrington, Caroline; Butt, Umar; Cvrljevic, Anna N.; Vainonen, Julia P.; Feringa, Femke M.; Gronroos, Tove J.; Gautam, Prson; Khan, Sofia; Sihto, Harri; Qiao, Xi; Pavic, Karolina; Connolly, Denise C.; Kronqvist, Pauliina; Elo, Laura L.; Maurer, Jochen; Wennerberg, Krister; Medema, Rene H.; Joensuu, Heikki; Peuhu, Emilia; de Visser, Karin; Narla, Goutham; Westermarck, Jukka (2021)
    Basal-like breast cancers (BLBC) are characterized by defects in homologous recombination (HR), deficient mitotic checkpoint, and high-proliferation activity. Here, we discover CIP2A as a candidate driver of BLBC. CIP2A was essential for DNA damage-induced initiation of mouse BLBC-like mammary tumors and for survival of HR-defective BLBC cells. CIP2A was dispensable for normal mammary gland development and for unperturbed mitosis, but selectively essential for mitotic progression of DNA damaged cells. A direct interaction between CIP2A and a DNA repair scaffold protein TopBP1 was identified, and CIP2A inhibition resulted in enhanced DNA damage-induced TopBP1 and RAD51 recruitment to chromatin in mammary epithelial cells. In addition to its role in tumor initiation, and survival of BRCA-deficient cells, CIP2A also drove proliferative MYC and E2F1 signaling in basal-like triple-negative breast cancer (BL-TNBC) cells. Clinically, high CIP2A expression was associated with poor patient prognosis in BL-TNBCs but not in other breast cancer subtypes. Small-molecule reactivators of PP2A (SMAP) inhibited CIP2A transcription, phenocopied the CIP2A-deficient DNA damage response (DDR), and inhibited growth of patient-derived BLBC xenograft. In summary, these results demonstrate that CIP2A directly interacts with TopBP1 and coordinates DNAdamage-induced mitotic checkpoint and proliferation, thereby driving BLBC initiation and progression. SMAPs could serve as a surrogate therapeutic strategy to inhibit the oncogenic activity of CIP2A in BLBCs. Significance: These results identify CIP2A as a nongenetic driver and therapeutic target in basal-like breast cancer that regulates DNA damage-induced G2-M checkpoint and proliferative signaling.
  • Kaustio, Meri; Nayebzadeh, Naemeh; Hinttala, Reetta; Tapiainen, Terhi; Astrom, Pirjo; Mamia, Katariina; Pernaa, Nora; Lehtonen, Johanna; Glumoff, Virpi; Rahikkala, Elisa; Honkila, Minna; Olsen, Paivi; Hassinen, Antti; Polso, Minttu; Al Sukaiti, Nashat; Al Shekaili, Jalila; Al Kindi, Mahmood; Al Hashmi, Nadia; Almusa, Henrikki; Bulanova, Daria; Haapaniemi, Emma; Chen, Pu; Suo-Palosaari, Maria; Vieira, Paivi; Tuominen, Hannu; Kokkonen, Hannaleena; Al Macki, Nabil; Al Habsi, Huda; Löppönen, Tuija; Rantala, Heikki; Pietiäinen, Vilja; Zhang, Shen-Ying; Renko, Marjo; Hautala, Timo; Al Farsi, Tariq; Uusimaa, Johanna; Saarela, Janna (2021)
    Background: Homozygous loss of DIAPH1 results in seizures, cortical blindness, and microcephaly syndrome (SCBMS). We studied 5 Finnish and 2 Omani patients with loss of DIAPH1 presenting with SCBMS, mitochondrial dysfunction, and immunodeficiency. Objective: We sought to further characterize phenotypes and disease mechanisms associated with loss of DIAPH1. Methods: Exome sequencing, genotyping and haplotype analysis, B- and T-cell phenotyping, in vitro lymphocyte stimulation assays, analyses of mitochondrial function, immunofluorescence staining for cytoskeletal proteins and mitochondria, and CRISPR-Cas9 DIAPH1 knockout in heathy donor PBMCs were used. Results: Genetic analyses found all Finnish patients homozygous for a rare DIAPH1 splice-variant (NM_005219:c.68411G>A) enriched in the Finnish population, and Omani patients homozygous for a previously described pathogenic DIAPH1 frameshift-variant (NM_005219:c.2769delT;p.F923fs). In addition to microcephaly, epilepsy, and cortical blindness characteristic to SCBMS, the patients presented with infection susceptibility due to defective lymphocyte maturation and 3 patients developed B-cell lymphoma. Patients' immunophenotype was characterized by poor lymphocyte activation and proliferation, defective B-cell maturation, and lack of naive T cells. CRISPR-Cas9 knockout of DIAPH1 in PBMCs from healthy donors replicated the T-cell activation defect. Patient-derived peripheral blood T cells exhibited impaired adhesion and inefficient microtubule-organizing center repositioning to the immunologic synapse. The clinical symptoms and laboratory tests also suggested mitochondrial dysfunction. Experiments with immortalized, patient-derived fibroblasts indicated that DIAPH1 affects the amount of complex IV of the mitochondrial respiratory chain. Conclusions: Our data demonstrate that individuals with SCBMS can have combined immune deficiency and implicate defective cytoskeletal organization and mitochondrial dysfunction in SCBMS pathogenesis.
  • Weber-Boyvat, Marion; Trimbuch, Thorsten; Shah, Saundarya; Jäntti, Jussi; Olkkonen, Vesa M.; Rosenmund, Christian (2021)
    OSBP-homologous proteins (ORPs, Oshp) are lipid binding/transfer proteins. Several ORP/Oshp localize to membrane contacts between the endoplasmic reticulum (ER) and the plasma membrane, where they mediate lipid transfer or regulate lipid-modifying enzymes. A common way in which they target contacts is by binding to the ER proteins, VAP/Scs2p, while the second membrane is targeted by other interactions with lipids or proteins. We have studied the cross-talk of secretory SNARE proteins and their regulators with ORP/Oshp and VAPA/Scs2p at ER-plasma membrane contact sites in yeast and murine primary neurons. We show that Oshp-Scs2p interactions depend on intact secretory SNARE proteins, especially Sec9p. SNAP-25/Sec9p directly interact with ORP/Osh proteins and their disruption destabilized the ORP/Osh proteins, associated with dysfunction of VAPA/Scs2p. DeletingOSH1-3in yeast or knocking down ORP2 in primary neurons reduced the oligomerization of VAPA/Scs2p and affected their multiple interactions with SNAREs. These observations reveal a novel cross-talk between the machineries of ER-plasma membrane contact sites and those driving exocytosis.
  • Mackenzie, Kathryn Kuligowska; Coelho, Livia Lopes; Lutken, Henrik; Mueller, Renate (2019)
    The PEBP family comprises proteins that function as key regulators of flowering time throughout the plant kingdom and they also regulate growth and plant architecture. Within the PEBP protein family, three subfamilies can be distinguished in angiosperms: MOTHER OF FT AND TFL1-like (MFT), FLOWERING LOCUS T-like (FT-like), and TERMINAL FLOWER1-like (TFL1-like). Taking advantage of the genome sequences available from K. fedtschenkoi and K. laxiflora, we performed computational analysis to identify the members of the PEBP gene family in these species. The analyses revealed the existence of 11 PEBP genes in K. fedtschenkoi and 18 in K. laxiflora, which are clustered in two clades: FT-like and TFL1-like. The PEBP genes had conserved gene structure and the proteins had highly conserved amino acid sequences in the positions crucial for the protein functions. The analysis of Ka/Ks ratio revealed that most recently duplicated genes are under positive selection. Despite being an economically important genus, the genetics underlying the regulation of flowering in Kalanchoe is poorly understood. The results of this study may provide a new insight into the molecular control of flowering that will allow further studies on flowering control in Kalanchoe.
  • Koskela, Elli Aurora; Sonsteby, Anita; Flachowsky, Henryk; Heide, Ola Mikal; Hanke, Magda-Viola; Elomaa, Paula; Hytönen, Timo (2016)
    The effects of daylength and temperature on flowering of the cultivated octoploid strawberry (Fragaria x ananassa Duch.) have been studied extensively at the physiological level, but information on the molecular pathways controlling flowering in the species is scarce. The flowering pathway has been studied at the molecular level in the diploid short-day woodland strawberry (F. vesca L.), in which the FLOWERING LOCUS T1 (FvFT1) SUPPRESSOR OF OVEREXPRESSION OF CONSTANS1 (FvSOC1)-TERMINAL FLOWER1 (FvTFL1) pathway is essential for the correct timing of flowering. In this work, we show by transgenic approach that the silencing of the floral repressor FaTFL1 in the octoploid short-day cultivar 'Elsanta' is sufficient to induce perpetual flowering under long days without direct changes in vegetative reproduction. We also demonstrate that although the genes FaFT1 and FaSOC1 show similar expression patterns in different cultivars, the regulation of FaTFL1 varies widely from cultivar to cultivar and is correlated with floral induction, indicating that the transcription of FaTFL1 occurs at least partially independently of the FaFT1-FaSOC1 module. Our results indicate that changing the expression patterns of FaTFL1 through biotechnological or conventional breeding approaches could result in strawberries with specific flowering and runnering characteristics including new types of everbearing cultivars.
  • Andres, Javier; Caruana, Julie; Liang, Jiahui; Samad, Samia; Monfort, Amparo; Liu, Zhongchi; Hytönen, Timo; Koskela, Elli A. (2021)
    Plant architecture is defined by fates and positions of meristematic tissues and has direct consequences on yield potential and environmental adaptation of the plant. In strawberries (Fragaria vesca L. and F. x ananassa Duch.), shoot apical meristems can remain vegetative or differentiate into a terminal inflorescence meristem. Strawberry axillary buds (AXBs) are located in leaf axils and can either remain dormant or follow one of the two possible developmental fates. AXBs can either develop into stolons needed for clonal reproduction or into branch crowns (BCs) that can bear their own terminal inflorescences under favorable conditions. Although AXB fate has direct consequences on yield potential and vegetative propagation of strawberries, the regulation of AXB fate has so far remained obscure. We subjected a number of woodland strawberry (F. vesca L.) natural accessions and transgenic genotypes to different environmental conditions and growth regulator treatments to demonstrate that strawberry AXB fate is regulated either by environmental or endogenous factors, depending on the AXB position on the plant. We confirm that the F. vesca GIBBERELLIN20-oxidase4 (FvGA20ox4) gene is indispensable for stolon development and under tight environmental regulation. Moreover, our data show that apical dominance inhibits the outgrowth of the youngest AXB as BCs, although the effect of apical dominance can be overrun by the activity of FvGA20ox4. Finally, we demonstrate that the FvGA20ox4 is photoperiodically regulated via FvSOC1 (F. vesca SUPPRESSOR OF OVEREXPRESSION OF CONSTANS1) at 18 degrees C, but at higher temperature of 22 degrees C an unidentified FvSOC1-independent pathway promotes stolon development. Environmental conditions and apical dominance dictate woodland strawberry plant architecture by regulating axillary bud fate.