). † These two authors contributed equally to this work. SummaryRecent studies of auxin response have focused on the functions of three sets of proteins: the auxin (Aux) response factors (ARFs), the Aux/IAAs, and the F-box protein TIR1. The ARF proteins bind DNA and directly activate or repress transcription of target genes while the Aux/IAA proteins repress ARF function. TIR1 is part of a ubiquitin protein ligase required for degradation of Aux/IAA proteins. Here we report the isolation and characterization of a novel mutant of Arabidopsis called axr5-1. Mutant plants are resistant to auxin and display a variety of auxin-related growth defects including defects in root and shoot tropisms. Further, the axr5-1 mutation results in a decrease in auxin-regulated transcription. The molecular cloning of AXR5 revealed that the gene encodes the IAA1 protein, a member of the Aux/IAA family of proteins. AXR5 is expressed throughout plant development consistent with the pleiotropic mutant phenotype. The axr5-1 mutation results in an amino acid substitution in conserved domain II of the protein, similar to gain-of-function mutations recovered in other members of this gene family. Biochemical studies show that IAA1/AXR5 interacts with TIR1 in an auxin-dependent manner. The mutation prevents this interaction suggesting that the mutant phenotype is caused by the accumulation of IAA1/AXR5. Our results provide further support for a model in which most members of the Aux/IAA family are targeted for degradation by SCF TIR1 in response to auxin.

Little is known about the transcriptional regulation of tumor angiogenesis, and tumor ECs (tECs) remain poorly characterized. Here, we studied the expression pattern of the transcription factor Sox17 in the vasculature of murine and human tumors and investigated the function of Sox17 during tumor angiogenesis using Sox17 genetic mouse models. Sox17 was specifically expressed in tECs in a heterogeneous pattern; in particular, strong Sox17 expression distinguished tECs with high VEGFR2 expression. Whereas overexpression of Sox17 in tECs promoted tumor angiogenesis and vascular abnormalities, Sox17 deletion in tECs reduced tumor angiogenesis and normalized tumor vessels, inhibiting tumor growth. Tumor vessel normalization by Sox17 deletion was long lasting, improved anticancer drug delivery into tumors, and inhibited tumor metastasis. Sox17 promoted endothelial sprouting behavior and upregulated VEGFR2 expression in a cell-intrinsic manner. Moreover, Sox17 increased the percentage of tumor-associated CD11b + Gr-1 + myeloid cells within tumors. The vascular effects of Sox17 persisted throughout tumor growth. Interestingly, Sox17 expression specific to tECs was also observed in highly vascularized human glioblastoma samples. Our findings establish Sox17 as a key regulator of tumor angiogenesis and tumor progression.

Rationale: Vascular endothelial growth factor (VEGF) signaling is a key pathway for angiogenesis and requires highly coordinated regulation. Although the Notch pathway-mediated suppression of excessive VEGF activity via negative feedback is well known, the positive feedback control for augmenting VEGF signaling remains poorly understood. Transcription factor Sox17 is indispensable for angiogenesis, but its association with VEGF signaling is largely unknown. The contribution of other Sox members to angiogenesis also remains to be determined. Objective: