Suppression of induced pluripotent stem cell generation by the p53–p21 pathway

Hong, Hyenjong; Takahashi, Kazutoshi; Ichisaka, Tomoko; Aoi, Takashi; Kanagawa, Osami; Nakagawa, Masato; Okita, Keisuke; Yamanaka, Shinya
August 2009
Nature;8/27/2009, Vol. 460 Issue 7259, p1132
Academic Journal
Induced pluripotent stem (iPS) cells can be generated from somatic cells by the introduction of Oct3/4 (also known as Pou5f1), Sox2, Klf4 and c-Myc, in mouse and in human. The efficiency of this process, however, is low. Pluripotency can be induced without c-Myc, but with even lower efficiency. A p53 (also known as TP53 in humans and Trp53 in mice) short-interfering RNA (siRNA) was recently shown to promote human iPS cell generation, but the specificity and mechanisms remain to be determined. Here we report that up to 10% of transduced mouse embryonic fibroblasts lacking p53 became iPS cells, even without the Myc retrovirus. The p53 deletion also promoted the induction of integration-free mouse iPS cells with plasmid transfection. Furthermore, in the p53-null background, iPS cells were generated from terminally differentiated T lymphocytes. The suppression of p53 also increased the efficiency of human iPS cell generation. DNA microarray analyses identified 34 p53-regulated genes that are common in mouse and human fibroblasts. Functional analyses of these genes demonstrate that the p53–p21 pathway serves as a barrier not only in tumorigenicity, but also in iPS cell generation.


Related Articles

  • Keeping p53 in check: essential and synergistic functions of Mdm2 and Mdm4. Marine, J.-C.; Francoz, S.; Maetens, M.; Wahl, G.; Toledo, F.; Lozano, G. // Cell Death & Differentiation;Jun2006, Vol. 13 Issue 6, p927 

    The article focuses on keeping p53 in check under functions of Mdm2 and Mdm4 proteins. In the absence of stress signals, the p53 protein is kept in check to allow normal cell proliferation and maintenance of cell viability. In this process, the critical importance are the two structurally...

  • Linking the p53 tumour suppressor pathway to somatic cell reprogramming. Kawamura, Teruhisa; Suzuki, Jotaro; Wang, Yunyuan V.; Menendez, Sergio; Morera, Laura Batlle; Raya, Angel; Wahl, Geoffrey M.; Belmonte, Juan Carlos Izpisúa // Nature;8/27/2009, Vol. 460 Issue 7259, p1140 

    Reprogramming somatic cells to induced pluripotent stem (iPS) cells has been accomplished by expressing pluripotency factors and oncogenes, but the low frequency and tendency to induce malignant transformation compromise the clinical utility of this powerful approach. We address both issues by...

  • The onset of p53 loss of heterozygosity is differentially induced in various stem cell types and may involve the loss of either allele. Shetzer, Y; Kagan, S; Koifman, G; Sarig, R; Kogan-Sakin, I; Charni, M; Kaufman, T; Zapatka, M; Molchadsky, A; Rivlin, N; Dinowitz, N; Levin, S; Landan, G; Goldstein, I; Goldfinger, N; Pe'er, D; Radlwimmer, B; Lichter, P; Rotter, V; Aloni-Grinstein, R // Cell Death & Differentiation;Sep2014, Vol. 21 Issue 9, p1419 

    p53 loss of heterozygosity (p53LOH) is frequently observed in Li-Fraumeni syndrome (LFS) patients who carry a mutant (Mut) p53 germ-line mutation. Here, we focused on elucidating the link between p53LOH and tumor development in stem cells (SCs). Although adult mesenchymal stem cells (MSCs)...

  • Inhibition of Breast Cancer Metastasis Suppressor 1 Promotes a Mesenchymal Phenotype in Lung Epithelial Cells That Express Oncogenic K-RasV12 and Loss of p53. Hall, Emily H.; Liu, Yuan; Xiao, Aizhen; Shock, Lisa; Brautigan, David L.; Mayo, Marty W.; Adusumilli, Prasad S.; Jones, David R. // PLoS ONE;Apr2014, Vol. 9 Issue 4, p1 

    Expression of the breast cancer metastasis suppressor 1 (BRMS1) protein is dramatically reduced in non-small cell lung cancer (NSCLC) cells and in primary human tumors. Although BRMS1 is a known suppressor of metastasis, the mechanisms through which BRMS1 functions to regulate cell migration and...

  • The TBC1D15 Oncoprotein Controls Stem Cell Self-Renewal through Destabilization of the Numb-p53 Complex. Feldman, Douglas E.; Chen, Chialin; Punj, Vasu; Machida, Keigo // PLoS ONE;Feb2013, Vol. 8 Issue 2, p1 

    Stem cell populations are maintained through self-renewing divisions in which one daughter cell commits to a specific fate while the other retains the multipotent characteristics of its parent. The p53 tumor suppressor, in conjunction with its interacting partner protein Numb, preserves this...

  • Ovarian carcinomas with genetic and epigenetic BRCA1 loss have distinct molecular abnormalities. Press, Joshua Z.; De Luca, Alessandro; Boyd, Niki; Young, Sean; Troussard, Armelle; Ridge, Yolanda; Kaurah, Pardeep; Kalloger, Steve E.; Blood, Katherine A.; Smith, Margaret; Spellman, Paul T.; Yuker Wang; Miller, Dianne M.; Horsman, Doug; Faham, Malek; Gilks, C. Blake; Gray, Joe; Huntsman, David G. // BMC Cancer;2008, Vol. 8, Special section p1 

    Background: Subclassification of ovarian carcinomas can be used to guide treatment and determine prognosis. Germline and somatic mutations, loss of heterozygosity (LOH), and epigenetic events such as promoter hypermethylation can lead to decreased expression of BRCA1/ 2 in ovarian cancers. The...

  • Out of the jaws of death: PRMT5 steers p53. Berger, Shelley L. // Nature Cell Biology;Dec2008, Vol. 10 Issue 12, p1389 

    The tumour suppressor p53 triggers either cell-cycle arrest or apoptosis. Now, arginine methylation joins a panoply of other post-translational modifications that regulate p53. PRMT5 mediates p53 methylation, which disposes the cell to arrest rather than death.

  • Mdm2-mediated ubiquitylation: p53 and beyond. Marine, J.-C.; Lozano, G. // Cell Death & Differentiation;Jan2010, Vol. 17 Issue 1, p93 

    The really interesting genes (RING)-finger-containing oncoprotein, Mdm2, is a promising drug target for cancer therapy. A key Mdm2 function is to promote ubiquitylation and proteasomal-dependent degradation of the tumor suppressor protein p53. Recent reports provide novel important insights into...

  • Savior and slayer: the two faces of p53. Bensaad, Karim; Vousden, Karen H. // Nature Medicine;Dec2005, Vol. 11 Issue 12, p1278 

    The article focuses on tumor suppressor protein p53. The tumor suppressor protein p53 prevents the development of cancer by inhibiting the proliferation of nascent cancer cells, which depends in part on the expression of genes that regulate cell-cycle arrest or apoptosis. There is also evidence...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics