TY - JOUR
T1 - MicroRNA-34a is dispensable for p53 function as teratogenesis inducer
AU - Mor, Eyal
AU - He, Lin
AU - Torchinsky, Arkady
AU - Shomron, Noam
N1 - Funding Information:
Acknowledgments The authors would like to acknowledge Avital gilam and Daphne Doron for their appreciated contribution. The Shomron laboratory is supported by the Wolfson Family charitable Fund; claire and Amedee Maratier Institute for the Study of Blindness and visual Disorders; Israel cancer Research Fund; earlier.org— friends for an earlier breast cancer test; I-cORe program of the planning and Budgeting committee of the Israel Science Foundation (grant No. 41/11).
PY - 2014/9
Y1 - 2014/9
N2 - The tumor suppressor protein p53 is a powerful regulator of the embryo's susceptibility to diverse teratogenic stimuli, functioning both as a teratogenesis inducer and suppressor. However, the targets that p53 engages to fulfill its functions remain largely undefined. We asked whether the microRNA (miRNA) miR-34 family, identified as one of the main targets of p53, mediates its function as a teratogenesis inducer. For this, pregnant ICR-, p53- and miR-34a-deficient mice, as well as rats, were exposed to 5-aza-2′- deoxycytidine (5-aza), a teratogen inducing limb reduction anomalies (LRA) of the hindlimbs in mice and either the hindlimbs or forelimbs in rats. Using hind- and forelimb buds of 5-aza-exposed embryos, we identified that the miR-34 family members are the most upregulated miRNAs in mouse and rat limb buds, with their increase level being significantly higher in limb buds destined for LRA. We showed that p53 mediates the 5-aza-induced miR-34 transcription followed by met proto-oncogene and growth-arrest-specific 1 target suppression in embryonic limb buds. We demonstrated that p53 regulates the teratogenic response to 5-aza acting as a teratogenesis inducer albeit miR-34a deletion does not affect the susceptibility of mice to 5-aza. Overall, our study thoroughly characterizes the expression and regulation of miR-34 family in teratogen-resistant and teratogen-sensitive embryonic structures and discusses the involvement of epigenetic miRNA-mediated pathway(s) in induced teratogenesis.
AB - The tumor suppressor protein p53 is a powerful regulator of the embryo's susceptibility to diverse teratogenic stimuli, functioning both as a teratogenesis inducer and suppressor. However, the targets that p53 engages to fulfill its functions remain largely undefined. We asked whether the microRNA (miRNA) miR-34 family, identified as one of the main targets of p53, mediates its function as a teratogenesis inducer. For this, pregnant ICR-, p53- and miR-34a-deficient mice, as well as rats, were exposed to 5-aza-2′- deoxycytidine (5-aza), a teratogen inducing limb reduction anomalies (LRA) of the hindlimbs in mice and either the hindlimbs or forelimbs in rats. Using hind- and forelimb buds of 5-aza-exposed embryos, we identified that the miR-34 family members are the most upregulated miRNAs in mouse and rat limb buds, with their increase level being significantly higher in limb buds destined for LRA. We showed that p53 mediates the 5-aza-induced miR-34 transcription followed by met proto-oncogene and growth-arrest-specific 1 target suppression in embryonic limb buds. We demonstrated that p53 regulates the teratogenic response to 5-aza acting as a teratogenesis inducer albeit miR-34a deletion does not affect the susceptibility of mice to 5-aza. Overall, our study thoroughly characterizes the expression and regulation of miR-34 family in teratogen-resistant and teratogen-sensitive embryonic structures and discusses the involvement of epigenetic miRNA-mediated pathway(s) in induced teratogenesis.
KW - Development
KW - Limbs
KW - Teratogens
KW - miR-34
KW - miRNA
KW - microRNA
KW - p53
UR - http://www.scopus.com/inward/record.url?scp=84906212554&partnerID=8YFLogxK
U2 - 10.1007/s00204-014-1223-9
DO - 10.1007/s00204-014-1223-9
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AN - SCOPUS:84906212554
SN - 0340-5761
VL - 88
SP - 1749
EP - 1763
JO - Archives of Toxicology
JF - Archives of Toxicology
IS - 9
ER -