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- Vasilaki, Eleftheria, et al.
(författare)
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Ras and TGF-beta signaling enhance cancer progression by promoting the Delta Np63 transcriptional program
- 2016
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Ingår i: Science Signaling. - : American Association for the Advancement of Science (AAAS). - 1945-0877 .- 1937-9145. ; 9:442
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Tidskriftsartikel (refereegranskat)abstract
- The p53 family of transcription factors includes p63, which is a master regulator of gene expression in epithelial cells. Determining whether p63 is tumor-suppressive or tumorigenic is complicated by isoform-specific and cellular context-dependent protein associations, as well as antagonism from mutant p53. Delta Np63 is an amino-terminal-truncated isoform, that is, the predominant isoform expressed in cancer cells of epithelial origin. In HaCaT keratinocytes, which have mutant p53 and Delta Np63, we found that mutant p53 antagonized Delta Np63 transcriptional activity but that activation of Ras or transforming growth factor-beta (TGF-beta) signaling pathways reduced the abundance of mutant p53 and strengthened target gene binding and activity of Delta Np63. Among the products of Delta Np63-induced genes was dual-specificity phosphatase 6 (DUSP6), which promoted the degradation of mutant p53, likely by dephosphorylating p53. Knocking down all forms of p63 or DUSP6 and DUSP7 (DUSP6/7) inhibited the basal or TGF-beta-induced or epidermal growth factor (which activates Ras)-induced migration and invasion in cultures of p53-mutant breast cancer and squamous skin cancer cells. Alternatively, overexpressing Delta Np63 in the breast cancer cells increased their capacity to colonize various tissues upon intracardiac injection in mice, and this was inhibited by knocking down DUSP6/7 in these Delta Np63-overexpressing cells. High abundance of Delta Np63 in various tumors correlated with poor prognosis in patients, and this correlation was stronger in patients whose tumors also had a mutation in the gene encoding p53. Thus, oncogenic Ras and TGF-beta signaling stimulate cancer progression through activation of the Delta Np63 transcriptional program.
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| 2. |
- Morikawa, Masato, et al.
(författare)
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BMP Sustains Embryonic Stem Cell Self-Renewal through Distinct Functions of Different Kruppel-like Factors
- 2016
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Ingår i: Stem Cell Reports. - : Elsevier BV. - 2213-6711. ; 6:1, s. 64-73
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Tidskriftsartikel (refereegranskat)abstract
- Bone morphogenetic protein (BMP) signaling exerts paradoxical roles in pluripotent stem cells (PSCs); it sustains self-renewal of mouse embryonic stem cells (ESCs), while it induces differentiation in other PSCs, including human ESCs. Here, we revisit the roles of BMP-4 using mouse ESCs (mESCs) in naive and primed states. SMAD1 and SMAD5, which transduce BMP signals, recognize enhancer regions together with KLF4 and KLF5 in naive mESCs. KLF4 physically interacts with SMAD1 and suppresses its activity. Consistently, a subpopulation of cells with active BMP-SMAD can be ablated without disturbing the naive state of the culture. Moreover, Smad1/5 double-knockout mESCs stay in the naive state, indicating that the BMP-SMAD pathway is dispensable for it. In contrast, the MEK5-ERK5 pathway mediates BMP-4-induced self-renewal of mESCs by inducing Klf2, a critical factor for the ground state pluripotency. Our study illustrates that BMP exerts its self-renewing effect through distinct functions of different Kruppel-like factors.
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