A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
UBR5 Is Coamplified with MYC in Breast Tumors and Encodes an Ubiquitin Ligase That Limits MYC-Dependent Apoptosis
Tekijät: Qiao X, Liu Y, Prada ML, Mohan AK, Gupta A, Jaiswal A, Sharma M, Merisaari J, Haikala HM, Talvinen K, Yetukuri L, Pylvänäinen JW, Klefstrom J, Kronqvist P, Meinander A, Aittokallio T, Hietakangas V, Eilers M, Westermarck J, Westermarck J
Kustantaja: AMER ASSOC CANCER RESEARCH
Julkaisuvuosi: 2020
Journal: Cancer Research
Tietokannassa oleva lehden nimi: CANCER RESEARCH
Lehden akronyymi: CANCER RES
Vuosikerta: 80
Numero: 7
Aloitussivu: 1414
Lopetussivu: 1427
Sivujen määrä: 14
ISSN: 0008-5472
eISSN: 1538-7445
DOI: https://doi.org/10.1158/0008-5472.CAN-19-1647
Rinnakkaistallenteen osoite: https://research.utu.fi/converis/portal/detail/Publication/47005529
For maximal oncogenic activity, cellular MYC protein levels need to be tightly controlled so that they do not induce apoptosis. Here, we show how ubiquitin ligase UBR5 functions as a molecular rheostat to prevent excess accumulation of MYC protein. UBR5 ubiquitinates MYC and its effects on MYC protein stability are independent of FBXW7. Silencing of endogenous UBR5 induced MYC protein expression and regulated MYC target genes. Consistent with the tumor suppressor function of UBR5 (HYD) in Drosophila, HYD suppressed dMYC-dependent overgrowth of wing imaginal discs. In contrast, in cancer cells, UBR5 suppressed MYC-dependent priming to therapy-induced apoptosis. Of direct cancer relevance, MYC and UBR5 genes were coamplified in MYC-driven human cancers. Functionally, UBR5 suppressed MYC-mediated apoptosis in p53-mutant breast cancer cells with UBR5/MYC coamplification. Furthermore, single-cell immunofluorescence analysis demonstrated reciprocal expression of UBR5 and MYC in human basal-type breast cancer tissues. In summary, UBR5 is a novel MYC ubiquitin ligase and an endogenous rheostat for MYC activity. In MYC-amplified, and p53-mutant breast cancer cells, UBR5 has an important role in suppressing MYC-mediated apoptosis priming and in protection from drug-induced apoptosis.Significance: These findings identify UBR5 as a novel MYC regulator, the inactivation of which could be very important for understanding of MYC dysregulation on cancer cells.
Ladattava julkaisu This is an electronic reprint of the original article. |  |
