title: IKAP/Elp1 involvement in cytoskeleton regulation and implication for familial dysautonomia.
abstract: Deficiency in the IKAP/Elp1 protein leads to the recessive sensory autosomal congenital neuropathy which is called familial dysautonomia (FD). This protein was originally identified as a role player in transcriptional elongation being a subunit of the RNAPII transcriptional Elongator multi-protein complex. Subsequently, IKAP/Elp1 was shown to play various functions in the cytoplasm. Here, we describe experiments performed with IKAP/Elp1 downregulated cell lines and FD-derived cells and tissues. Immunostaining of the cytoskeleton component α-tubulin in IKAP/Elp1 downregulated cells revealed disorganization of the microtubules (MTs) that was reflected in aberrant cell shape and process formation. In contrast to a recent report on the decrease in α-tubulin acetylation in IKAP/Elp1 downregulated cells, we were unable to observe any effect of IKAP/Elp1 deficiency on α-tubulin acetylation in the FD cerebrum and in a variety of IKAP/Elp1 downregulated cell lines. To explore possible candidates involved in the observed aberrations in MTs, we focused on superior cervical ganglion-10 protein (SCG10), also called STMN2, which is known to be an MT destabilizing protein. We have found that SCG10 is upregulated in the IKAP/Elp1-deficient FD cerebrum, FD fibroblasts and in IKAP/Elp1 downregulated neuroblastoma cell line. To better understand the effect of IKAP/Elp1 deficiency on SCG10 expression, we investigated the possible involvement of RE-1-silencing transcription factor (REST), a known repressor of the SCG10 gene. Indeed, REST was downregulated in the IKAP/Elp1-deficient FD cerebrum and IKAP/Elp1 downregulated neuroblastoma cell line. These results could shed light on a possible link between IKAP/Elp1 deficiency and cytoskeleton destabilization.
authors.affiliation: Department of Developmental Biology and Cancer Research, Institute of Medical Research Israel-Canada, The Hebrew University Hadassah Medical School, Jerusalem, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Cheishvili
authors.forename: Channa
authors.initials: C
authors.lastname: Maayan
authors.forename: Rachel
authors.initials: R
authors.lastname: Cohen-Kupiec
authors.forename: Sharon
authors.initials: S
authors.lastname: Lefler
authors.forename: Miguel
authors.initials: M
authors.lastname: Weil
authors.forename: Gil
authors.initials: G
authors.lastname: Ast
authors.forename: Aharon
authors.initials: A
authors.lastname: Razin
mesh_terms: D000107:Acetylation; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D048430:Cell Shape; D054022:Cerebrum / Q000378:metabolism; D002648:Child; D004402:Dysautonomia, Familial / Q000378:metabolism / Q000473:pathology*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000378:metabolism; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism*; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016501:Neurites / Q000378:metabolism; D034622:RNA Interference; D012097:Repressor Proteins / Q000378:metabolism; D050777:Stathmin; D035602:Transcriptional Elongation Factors; D014404:Tubulin / Q000378:metabolism; D015854:Up-Regulation; D000099229:RE1-Silencing Transcription Factor
chemical_list: D002352:Carrier Proteins; D051548:Histone Acetyltransferases; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; D050777:Stathmin; D035602:Transcriptional Elongation Factors; D014404:Tubulin; D000099229:RE1-Silencing Transcription Factor; C114720:Elp1 protein, human; C063314:STMN2 protein, human; C538729:ELP3 protein, human