Abstract:
:The ubiquitin ligase Siah2 has been shown to regulate prolyl hydroxylase 3 (PHD3) stability with concomitant effect on HIF-1alpha availability. Because HIF-1alpha is implicated in tumorigenesis and metastasis, we used SW1 mouse melanoma cells, which develop primary tumors with a propensity to metastasize, in a syngeneic mouse model to assess a possible role for Siah2 in these processes. Inhibiting Siah2 activity by expressing a peptide designed to outcompete association of Siah2-interacting proteins reduced metastasis through HIF-1alpha without affecting tumorigenesis. Conversely, inhibiting Siah2 activity by means of a dominant-negative Siah2 RING mutant primarily reduced tumorigenesis through the action of Sprouty 2, a negative regulator of Ras signaling. Consistent with our findings, reduced expression of PHD3 and Sprouty2 was observed in more advanced stages of melanoma tumors. Using complementary approaches, our data establish the role of Siah2 in tumorigenesis and metastasis by HIF-dependent and -independent mechanisms.
journal_name
Proc Natl Acad Sci U S Aauthors
Qi J,Nakayama K,Gaitonde S,Goydos JS,Krajewski S,Eroshkin A,Bar-Sagi D,Bowtell D,Ronai Zdoi
10.1073/pnas.0804063105subject
Has Abstractpub_date
2008-10-28 00:00:00pages
16713-8issue
43eissn
0027-8424issn
1091-6490pii
0804063105journal_volume
105pub_type
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