Regulation and functions of basic helix-loop-helix transcription factors in neuroblastoma cells

Research output: ThesisDoctoral Thesis (compilation)

Abstract

Neuroblastoma is a childhood tumor derived from primordial neural crest cells. The tumor cells exhibit a phenotype similar to that of developing neuroblasts, which indicates that the tumor arises due to perturbed differentiation of the sympathetic nervous system. It is well established that transcription factors control the steps leading to neuronal differentiation, and a number of basic helix-loop-helix (bHLH) proteins have been implicated in this process. To understand the genesis of neuroblastoma, it is essential to elucidate the transcriptional cascades involved in regulating neuronal differentiation. The present studies focused mainly on the role and function of the bHLH transcription factor human achaete-scute homologue 1 (HASH-1) in neuroblastoma cells. Two novel HASH-1-interacting proteins were isolated: the broadly expressed E2-2 and the ubiquitin-related ubiquilin-1. We found that the bHLH protein E2-2 associates with HASH-1 to form a functional, transactivating complex that may be involved in neurogenesis. It has been suggested that ubiquilin-1 participates in protein turnover, which agrees with our finding that ubiquilin-1 promotes accumulation of HASH-1. Our results also establish that Id proteins (i.e., HLH proteins lacking the basic domain) are expressed in neuroblastoma cells and are down-regulated during induced differentiation of these cells, and they interact with HES-1, but not with HASH-1 or dHAND. Furthermore, we discovered that neuroblastoma cells express O/E-1 and O/E-2, and that the DNA-binding activity of these proteins are increased during induced differentiation of neuroblastoma cells. In addition, we identified CgA and SCG10, as novel neuronal target genes of O/E-1. Much remains to be learned about how the bHLH proteins act in synergy with other transcriptional regulators and in this thesis novel interactions and connections are described.

Details

Authors
  • Paula Persson
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology

Keywords

  • oncology, Cytology, Id, Olf/EBF, ubiquilin-1, HASH-1, bHLH, Neuroblastoma, neuronal differentiation, cancer, onkologi, cancerology, Cytologi
Original languageEnglish
QualificationDoctor
Awarding Institution
Supervisors/Assistant supervisor
  • [unknown], [unknown], Supervisor, External person
Award date2002 Oct 4
Publisher
  • Paula Persson, Skvadronsg 27, 217 49 Malmö,
Print ISBNs91-628-5305-8
Publication statusPublished - 2002
Publication categoryResearch

Bibliographic note

Defence details Date: 2002-10-04 Time: 10:15 Place: Lilla aulan, MFC, U-MAS, Malmö External reviewer(s) Name: Ball, Douglas W. Title: Dr. Affiliation: [unknown] --- Article: I Paula Persson, Annika Jögi, Anna Grynfeld, Sven Påhlman and Håkan Axelson. HASH-1 and E2-2 are expressed in human neuroblastoma cells and form a functional complex. Biochem. Biophys. Res. Commun. 274,22-31 (2000). Article: II Annika Jögi*, Paula Persson*, Anna Grynfeld, Sven Påhlman and Håkan Axelson. Modulation of basic helix-loop-helix transcription complex formation by Id proteins during neuronal differentiation. J. Biol. Chem. 277:11, 9118-9126 (2002). *(These authors contributed equally to this work.) Article: III Paula Persson, Marie-Thérése Stockhausen, Sven Påhlman and Håkan Axelson. Ubiquilin-1 is a novel HASH-1-complexing protein that regulates levels of neuronal bHLH transcription factors. Submitted. Article: IV Paula Persson, Jens Nygren, Ramiro Gisler, Håkan Axelson and Mikael Sigvardsson. Olf/EBF proteins are expressed in neuroblastoma cells and interact directly with the Chromogranin A and SCG10 promoters. Manuscript. The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Molecular Medicine (013031200)