He Zhiwei, Cho Yong-Yeon, Ma Wei-Ya, Choi Hong Seok, Bode Ann M, Dong Zigang
Hormel Institute, University of Minnesota, Austin, Minnesota 55912, USA.
J Biol Chem. 2005 Jan 28;280(4):2446-54. doi: 10.1074/jbc.M402053200. Epub 2004 Nov 10.
Ultraviolet B (UVB) induces phosphorylation of histone H3 at serine 10, and mitogen-activated protein kinases are involved in this signal transduction pathway. Here we provide evidence that Fyn kinase, a member of the Src kinase family, is involved in the UVB-induced phosphorylation of histone H3 at serine 10. UVB distinctly increased Fyn kinase activity and phosphorylation. Fyn kinase inhibitors 4-amino-5-(4-chlorophenyl)-7(t-butyl)pyrazol(3,4-d)pyramide and leflunomide, an Src kinase inhibitor, suppressed both UVB-induced phosphorylation of histone H3 at serine 10 and Fyn kinase activity and phosphorylation. UVB-induced phosphorylation of histone H3 at serine 10 was blocked by either a dominant-negative mutant of Fyn (DNM-Fyn) kinase or small interfering RNA of Fyn kinase. UVB-induced phosphorylation and activities of ERKs and protein kinase B/Akt were markedly inhibited by DNM-Fyn kinase. However, DNM-Fyn kinase did not inhibit UVB-induced phosphorylation of p38 MAPK or c-Jun N-terminal kinases. Active Fyn kinase phosphorylated histone H3 at serine 10 in vitro, and the phosphorylated Fyn kinase could translocate into the nucleus of HaCaT cells. These results indicate that Fyn kinase plays a key role in the UVB-induced phosphorylation of histone H3 at serine 10.
紫外线B（UVB）可诱导组蛋白H3的丝氨酸10位点发生磷酸化，且丝裂原活化蛋白激酶参与这一信号转导途径。在此，我们提供证据表明，Src激酶家族成员Fyn激酶参与UVB诱导的组蛋白H3丝氨酸10位点的磷酸化。UVB显著增加Fyn激酶活性和磷酸化水平。Fyn激酶抑制剂4-氨基-5-（4-氯苯基）-7-（叔丁基）吡唑并[3,4-d]嘧啶以及Src激酶抑制剂来氟米特，均可抑制UVB诱导的组蛋白H3丝氨酸10位点的磷酸化以及Fyn激酶活性和磷酸化。UVB诱导的组蛋白H3丝氨酸10位点的磷酸化，可被Fyn激酶的显性负性突变体（DNM-Fyn）或Fyn激酶的小干扰RNA阻断。DNM-Fyn激酶可显著抑制UVB诱导的细胞外信号调节激酶（ERK）和蛋白激酶B/Akt的磷酸化及活性。然而，DNM-Fyn激酶并不抑制UVB诱导的p38丝裂原活化蛋白激酶（p38 MAPK）或c-Jun氨基末端激酶（c-Jun N-terminal kinases）的磷酸化。活性Fyn激酶可在体外使组蛋白H3的丝氨酸10位点发生磷酸化，且磷酸化的Fyn激酶可转位至HaCaT细胞的细胞核内。这些结果表明，Fyn激酶在UVB诱导的组蛋白H3丝氨酸10位点的磷酸化过程中起关键作用。
