The transcription factor GLI1 activates the expression of SOX9, and both proteins are known to contribute to the formation of pancreatic ductal adenocarcinomas (PDAs). However, the mechanism by which SOX9 functions downstream of GLI1 has thus far not been well understood. Here (p. 1123), J. Michael Ruppert and colleagues report a positive-feedback interaction between these two factors. Their data show that SOX9 stabilises GLI1 protein levels independently of effects on GLI1 transcription in human PDA cells. In the absence of SOX9, GLI1 is degraded by the proteasome. The degradation of GLI1 is known to be regulated through the E3 ubiquitin ligase SCFβ-TrCP, and the authors now find that GLI1 and SOX9 interact in a mutually exclusive manner with different protein motifs in the β-TrCP subunit of the E3 ligase. In addition, SOX9 disrupts the interaction between the β-TrCP and SKP1 subunits of SCFβ-TrCP. As the authors show, knockdown of SOX9 increases the half-life of β-TrCP and reduces the malignant properties of PDA cells in vitro; the latter effect is reversed by co-suppression of β-TrCP. Both SOX9 and GLI1 are required to maintain PDA cancer stem cells (CSCs), and knockdown of either protein results in very similar expression profiles of CSC markers. SOX9 knockdown also reduces the abundance of other SCFβ-TrCP targets. Taken together, these data provide important insights into the regulation of SOX9 and GLI1 in human cancers.
SOX9 and GLI1 cooperate in cancer
SOX9 and GLI1 cooperate in cancer. J Cell Sci 15 March 2015; 128 (6): e0605. doi:
Download citation file:
Advertisement
Cited by
Call for papers - Cilia and Flagella: from Basic Biology to Disease
We are welcoming submissions for our upcoming special issue: Cilia and Flagella: from Basic Biology to Disease. This issue will be coordinated by two Guest Editors: Pleasantine Mill (University of Edinburgh) and Lotte Pedersen (University of Copenhagen). Submission deadline: 1 March 2025.
Biologists @ 100 - join us in Liverpool in March 2025
We are excited to invite you to a unique scientific conference, celebrating the 100-year anniversary of The Company of Biologists, and bringing together our different communities. The conference will incorporate the Spring Meetings of the BSCB and the BSDB, the JEB Symposium Sensory Perception in a Changing World and a DMM programme on antimicrobial resistance. Find out more and register your interest to join us in March 2025 in Liverpool, UK.
Principles and regulation of mechanosensing
Mechanics play a fundamental role in cell physiology and represent physical mechanisms which cells use to influence function from the molecular to tissue scale. In this Review, Stefano Sala and colleagues clearly define mechanosensing and mechanotransduction, illustrate various mechanosensing mechanisms and discuss methods that cells use to regulate these processes.
JCS-FocalPlane Training Grants
Early-career researchers - working in an area covered by JCS - who would like to attend a microscopy training course, please apply. Deadline dates for 2024 applications: 7 September (decision by week commencing 8 October 2024); 22 November (decision by week commencing 16 December).
HIV-1 assembly – when virology meets biophysics
Claire Lacouture and colleagues review mechanisms of assembly of the HIV-1 structural protein Gag from biophysical and biological perspectives. The researchers highlight how HIV-1 Gag hijacks host cell factors associated with cortical actin machinery to make new viral particles.