Cdk5/p35 phosphorylates mSds3 and regulates mSds3-mediated repression of transcription.
Cyclin-dependent kinase 5 (Cdk5), a serine/threonine kinase that displays kinase activity predominantly in neurons, is activated by two non-cyclin activators, p35 or p39. Here, we report a physical and functional interaction between the Cdk5/p35 complex and mouse Sds3 (mSds3), an essential component of mSin3-histone deacetylase (HDAC) co-repressor complex. mSds3 binds to p35 both in vitro and in vivo, enabling active Cdk5 to phosphorylate mSds3 at serine 228. A mSds3 S228A mutant retained mSin3 binding activity, but its dimerization was not greatly enhanced by p35 when compared with wild type. Notably, p35 overexpression augmented mSds3-mediated transcriptional repression in vitro. Interestingly, mutational studies revealed that the ability of exogenous mSds3 to rescue cell growth and viability in mSds3 null cells correlates with its ability to be phosphorylated by Cdk5. The identification of mSds3 as a substrate of the Cdk5/p35 complex reveals a new regulatory mechanism in controlling the mSin3-HDAC transcriptional repressor activity and provides a new potential therapeutic means to inhibit specific HDAC activities in disease.
Li
Zhen
Z
Department of Biochemistry, Biotechnology Research Institute and Molecular Neuroscience Center, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong, China.
David
Gregory
G
Hung
Kwok-Wang
KW
DePinho
Ronald A
RA
Fu
Amy K Y
AK
Ip
Nancy Y
NY
D000818:Animals; D015152:Blotting, Northern; D001923:Brain Chemistry; D019556:COS Cells; D002460:Cell Line; D002461:Cell Line, Transformed; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D019281:Dimerization; D005982:Glutathione Transferase / Q000235:genetics; D006655:Histone Deacetylases / Q000378:metabolism; D051379:Mice; D009132:Muscles / Q000737:chemistry; D016296:Mutagenesis; D041681:NIH 3T3 Cells; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000032:analysis; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D014162:Transfection; D020798:Two-Hybrid System Techniques
D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; C491870:Sap30 protein, mouse; C497354:Sds3 protein, mouse; C089495:neuronal Cdk5 activator (p25-p35); D012694:Serine; D005982:Glutathione Transferase; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D018844:Cyclin-Dependent Kinases; D006655:Histone Deacetylases