title: Syntenin-mediated regulation of Sox4 proteasomal degradation modulates transcriptional output.
abstract: The transcription factor Sox4 is aberrantly expressed in many human tumors and can modulate tumorigenesis and metastases of murine tumors in vivo. However, mechanisms that control Sox4 function remain poorly defined. It has recently been observed that DNA damage increases Sox4 protein expression independently of Sox4 mRNA levels, suggesting an as yet undefined post-transcriptional mechanism regulating Sox4 expression and functionality. Here, we show that Sox4 protein is rapidly degraded by the proteasome as indicated by pharmacological inhibition with Mg132 and epoxymycin. Sox4 half-life was found to be less than 1 h as evident by inhibition of protein synthesis using cycloheximide. Ectopic expression of Sox4 deletion mutants revealed that the C-terminal 33 residues of Sox4 were critical in modulating its degradation in a polyubiquitin-independent manner. Syntenin, a Sox4 binding partner, associates with this domain and was found to stabilize Sox4 expression. Syntenin-induced stabilization of Sox4 correlated with Sox4-syntenin relocalization to the nucleus, where both proteins accumulate. Syntenin overexpression or knockdown in human tumor cell lines was found to reciprocally modulate Sox4 protein expression and transcriptional activity implicating its role as a regulator of Sox4. Taken together, our data demonstrate that the Sox4 C-terminal domain regulates polyubiquitin-independent proteasomal degradation of Sox4 that can be modulated by interaction with syntenin. As aberrant Sox4 expression has been found associated with many human cancers, modulation of Sox4 proteasomal degradation may impact oncogenesis and metastatic properties of tumors.
authors: Department of Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: J M
authors: JM
authors: Beekman
authors: S J
authors: SJ
authors: Vervoort
authors: F
authors: F
authors: Dekkers
authors: M E
authors: ME
authors: van Vessem
authors: S
authors: S
authors: Vendelbosch
authors: A
authors: A
authors: Brugulat-Panès
authors: J
authors: J
authors: van Loosdregt
authors: A K
authors: AK
authors: Braat
authors: P J
authors: PJ
authors: Coffer
mesh_terms: D020816:Amino Acid Motifs; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional; D055751:SOXC Transcription Factors / Q000378:metabolism*; D053676:Syntenins / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D055751:SOXC Transcription Factors; D053676:Syntenins; D046988:Proteasome Endopeptidase Complex