The RING finger E3 ubiquitin ligase Siah2 is implicated in control of diverse cellular biological events, including MAPK signaling and hypoxia. Here we demonstrate that Siah2 is subject to regulation by the deubiquitinating enzyme USP13. Overexpression of USP13 increases Siah2 stability by attenuating its autodegradation. Consequently, the ability of Siah2 to target its substrates prolyl hydroxylase 3 and Spry2 (Sprouty2) for ubiquitin-mediated proteasomal degradation is attenuated. Conversely, inhibition of USP13 expression with corresponding shRNA decreases the stability of both Siah2 and its substrate Spry2. Thus, USP13 limits Siah2 autodegradation and its ubiquitin ligase activity against its target substrates. Strikingly, the effect of USP13 on Siah2 is not mediated by its isopeptidase activity: mutations in its ubiquitin-binding sequences positioned within the ubiquitin-specific processing protease and ubiquitin-binding domains, but not within putative catalytic sites, abolish USP13 binding to and effect on Siah2 autodegradation and targeted ubiquitination. Notably, USP13 expression is attenuated in melanoma cells maintained under hypoxia, thereby relieving Siah2 inhibition and increasing its activity under low oxygen levels. Significantly, on melanoma tissue microarray, high nuclear expression of USP13 coincided with high nuclear expression of Siah2. Overall, this study identifies a new layer of Siah2 regulation mediated by USP13 binding to ubiquitinated Siah2 protein with a concomitant inhibitory effect on its activity under normoxia.Siah proteins are RING finger E3 ubiquitin ligases implicated in the ubiquitination and proteasome-dependent degradation of substrate molecules, which also limit their own availability through self-ubiquitination and degradation (1-3). Siah was first identified in Drosophila melanogaster as seven in absentia (sina), which regulates formation of the R7 photoreceptor through control of tramtrack stability (4, 5). Three murine Siah genes (Siah1a, Siah1b, and Siah2) share significant homology with the two human (SIAH1 and SIAH2) orthologues (6, 7).Siah2 is an important regulator of pathways activated under stress and hypoxia. Among substrates reportedly regulated by Siah under these conditions are TRAF2, ␣-ketoglutarate dehydrogenase, Spry2 (Sprouty2), and two of the three prolyl hydroxylases (8 -10). Given the role of PHD proteins as oxygen sensors and regulators of HIF1␣, the master transcription factor responding to hypoxia, Siah is implicated in the control of hypoxia, particularly within the range of 2-6% oxygen at which PHD proteins retain sufficient activity (11,12). The role of Siah2 in tumor development has been extensively studied. Inhibition of Siah reportedly attenuates breast, pancreatic, lung, prostate, and melanoma tumors (13-16). Mechanistically, Siah2 contributes to tumor development and metastasis via its control of diverse substrates, as shown in a melanoma model (14).A search for novel Siah2 interacting factors led to identification of the isopeptidase USP13 ...
Subcutanous panniculitis–like T cell lymphoma (STCL) is a rare clinical entity which simulates panniculitis and can present with an aggressive clinical course. STCL is divided two major subgroups (αβ-STCL and γδ-STCL), according the T cell receptor expression on the malignant T cells. γδ-STCL is often associated with a more aggressive course and poor prognosis with an 11% 5-yr survival in a retrospective study of 20 cases, only 6 of which were confirmed by TCRδ -1 staining.1 We report our results from 10 patients with STCL, 2 BetaF1+ (αβ-STCL), 8 γδ-STCL. The median age at presentation was 43 (25–63); 7 of 10 were female. Immunohistochemical studies and TCR gene rearrangements (TCRR) were performed on all patients. Cytotoxic T-cell markers were expressed in all pts (TIA-1 in 8 of 10 and Granzyme B in 5). Six were CD8+ and 3 were CD3+CD4−CD8−. CD56 expression was detected in 3. All demonstrated clonal TCRR. All pts presented with skin nodules or ulcerations, and 3 had visceral involvement (blood/bone marrow in 2, liver in 1). Three patients (2αβ-STCL and γδ-STCL) were treated initially with denileukin diftitox; one each with αβ- and γδ- disease had PR on therapy and have been maintained without PD. Seven patients were treated with cytotoxic chemotherapy regimens. Four of 7 achieved a remission after EPOCH (2), denileukin diftitox-CHOP (1) or pentostatin/cyclophosphamide followed by alemtuzumab (1). Four pts (1 with refractory ab-STCL, 2 with refractory gd-STCL, and 1 with γδ-STCL in first CR after denileukin diftitox-CHOP) underwent allogeneic hematopoietic stem cell (HSCT) from matched-related donors. Two patients are alive 6 and 13 months after HSCT with no evidence of disease; 1 patient died in CR from infectious complications of HSCT, and 1 relapsed 6 mo after HSCT and died from PD. At a median follow up of 3 yrs from diagnosis, 8 pts (80%) are alive, including the 2 pts with αβ-STCL and 6 of 8 pts with γδ-STCL. In summary, while γδ-STCL is reported in retrospective studies to have a poor prognosis, we demonstrate that aggressive therapies along with the incorporation of novel T-cell directed agents such as denileukin diftitox and alemtuzumab into treatment regimens and the use of allogeneic HSCT as a potentially curative therapy are promising approaches for these patients.
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