Abstract
The elongation stage of transcription is highly regulated in metazoans. We previously purified the AFF1- and AFF4-containing super elongation complex (SEC) as a major regulator of development and cancer pathogenesis. Here, we report the biochemical isolation of SEC-like 2 (SEC-L2) and SEC-like 3 (SEC-L3) containing AFF2 and AFF3 in association with P-TEFb, ENL/MLLT1, and AF9/MLLT3. The SEC family members demonstrate high levels of polymerase II (Pol II) C-terminal domain kinase activity; however, only SEC is required for the proper induction of the HSP70 gene upon stress. Genome-wide mRNA-Seq analyses demonstrated that SEC-L2 and SEC-L3 control the expression of different subsets of genes, while AFF4/SEC plays a more dominant role in rapid transcriptional induction in cells. MYC is one of the direct targets of AFF4/SEC, and SEC recruitment to the MYC gene regulates its expression in different cancer cells, including those in acute myeloid or lymphoid leukemia. These findings suggest that AFF4/SEC could be a potential therapeutic target for the treatment of leukemia or other cancers associated with MYC overexpression.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Base Sequence
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Cell Line
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Gene Expression Regulation
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Gene Knockdown Techniques
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Genes, myc
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HEK293 Cells
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HSP70 Heat-Shock Proteins / genetics
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Humans
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Jurkat Cells
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Leukemia / genetics
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Leukemia / metabolism
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Multiprotein Complexes / genetics
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Multiprotein Complexes / metabolism
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Positive Transcriptional Elongation Factor B / genetics
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Positive Transcriptional Elongation Factor B / metabolism
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RNA Polymerase II / metabolism*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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RNA, Neoplasm / genetics
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RNA, Neoplasm / metabolism
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Repressor Proteins / antagonists & inhibitors
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Transcription, Genetic
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Transcriptional Elongation Factors / metabolism*
Substances
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AFF2 protein, human
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AFF3 protein, human
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AFF4 protein, human
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HSP70 Heat-Shock Proteins
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Multiprotein Complexes
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Nuclear Proteins
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RNA, Messenger
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RNA, Neoplasm
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Repressor Proteins
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Transcriptional Elongation Factors
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Positive Transcriptional Elongation Factor B
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RNA Polymerase II