Bax, Bcl2, and p53 Differentially Regulate Neomycin- and Gentamicin-Induced Hair Cell Death in the Zebrafish Lateral Line View Full Text


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Article Info

DATE

2013-07-03

AUTHORS

Allison B. Coffin, Edwin W. Rubel, David W. Raible

ABSTRACT

Sensorineural hearing loss is a normal consequence of aging and results from a variety of extrinsic challenges such as excessive noise exposure and certain therapeutic drugs, including the aminoglycoside antibiotics. The proximal cause of hearing loss is often death of inner ear hair cells. The signaling pathways necessary for hair cell death are not fully understood and may be specific for each type of insult. In the lateral line, the closely related aminoglycoside antibiotics neomycin and gentamicin appear to kill hair cells by activating a partially overlapping suite of cell death pathways. The lateral line is a system of hair cell-containing sense organs found on the head and body of aquatic vertebrates. In the present study, we use a combination of pharmacologic and genetic manipulations to assess the contributions of p53, Bax, and Bcl2 in the death of zebrafish lateral line hair cells. Bax inhibition significantly protects hair cells from neomycin but not from gentamicin toxicity. Conversely, transgenic overexpression of Bcl2 attenuates hair cell death due to gentamicin but not neomycin, suggesting a complex interplay of pro-death and pro-survival proteins in drug-treated hair cells. p53 inhibition protects hair cells from damage due to either aminoglycoside, with more robust protection seen against gentamicin. Further experiments evaluating p53 suggest that inhibition of mitochondrial-specific p53 activity confers significant hair cell protection from either aminoglycoside. These results suggest a role for mitochondrial p53 activity in promoting hair cell death due to aminoglycosides, likely upstream of Bax and Bcl2. More... »

PAGES

645-659

References to SciGraph publications

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  • 2003-05-06. Neomycin-Induced Hair Cell Death and Rapid Regeneration in the Lateral Line of Zebrafish (Danio rerio) in JOURNAL OF THE ASSOCIATION FOR RESEARCH IN OTOLARYNGOLOGY
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  • 2008-05-30. Hsp70 Inhibits Aminoglycoside-Induced Hair Cell Death and is Necessary for the Protective Effect of Heat Shock in JOURNAL OF THE ASSOCIATION FOR RESEARCH IN OTOLARYNGOLOGY
  • 2006-03-17. Dissecting p53-dependent apoptosis in CELL DEATH & DIFFERENTIATION
  • 2001-10-30. Bax and other pro-apoptotic Bcl-2 family "killer-proteins" and their victim the mitochondrion in CELL AND TISSUE RESEARCH
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  • 2006-07-23. Small-molecule inhibitor of p53 binding to mitochondria protects mice from gamma radiation in NATURE CHEMICAL BIOLOGY
  • 2006-08-04. Functional characterization of the Bcl-2 gene family in the zebrafish in CELL DEATH & DIFFERENTIATION
  • 2008-04-11. BIM and other BCL-2 family proteins exhibit cross-species conservation of function between zebrafish and mammals in CELL DEATH & DIFFERENTIATION
  • 2008-10-27. The p53 family and programmed cell death in ONCOGENE
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1007/s10162-013-0404-1

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    44 schema:description Sensorineural hearing loss is a normal consequence of aging and results from a variety of extrinsic challenges such as excessive noise exposure and certain therapeutic drugs, including the aminoglycoside antibiotics. The proximal cause of hearing loss is often death of inner ear hair cells. The signaling pathways necessary for hair cell death are not fully understood and may be specific for each type of insult. In the lateral line, the closely related aminoglycoside antibiotics neomycin and gentamicin appear to kill hair cells by activating a partially overlapping suite of cell death pathways. The lateral line is a system of hair cell-containing sense organs found on the head and body of aquatic vertebrates. In the present study, we use a combination of pharmacologic and genetic manipulations to assess the contributions of p53, Bax, and Bcl2 in the death of zebrafish lateral line hair cells. Bax inhibition significantly protects hair cells from neomycin but not from gentamicin toxicity. Conversely, transgenic overexpression of Bcl2 attenuates hair cell death due to gentamicin but not neomycin, suggesting a complex interplay of pro-death and pro-survival proteins in drug-treated hair cells. p53 inhibition protects hair cells from damage due to either aminoglycoside, with more robust protection seen against gentamicin. Further experiments evaluating p53 suggest that inhibition of mitochondrial-specific p53 activity confers significant hair cell protection from either aminoglycoside. These results suggest a role for mitochondrial p53 activity in promoting hair cell death due to aminoglycosides, likely upstream of Bax and Bcl2.
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