John H. Frenster ^{1, @} and Jeannette A. Hovsepian ^{2, @}

Departments of ¹ Medicine and of ² Radiology, Stanford University School of Medicine, Stanford, California  94305,

^@ Present Addresses: Activator RNA  Research, Physicians’ Educational Series, Atherton, CA  94027-5446
Phone:  +1 650 367 6483;   Fax:  +1 650 364 1773;   e-mail:   frenster@euchromatin.net

* Supported in part by a USPHS Research Career Development Award (CA-17857) from the National Cancer Institute to J.H.F.

Adult neoplasms often re-express genes normally expressed only during embryogenesis. The re-appearance of RNA transcripts and protein translates from these embryonic genes within normal adult cells may play a role in oncogenesis, metastases, and response to therapy of these adult cells. For example, in the study of human non-small cell lung cancer (NSCLC), it has been observed that activity of the embryonic gene enhancer let-7  is often deficient, and that when let-7 is added back to such cancer cells in culture, the functional phenotype of the cancer cells is normalized, (Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endoh H, Harano T, Yatabe Y, Nagino M, Nimura Y, Mitsudomi T,  and Takahashi T, (2004), “Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival”, Cancer Res. 64: 3753–3756).  let-7 is an active locus in promoting cell differentition and maturation in embryonic cells, and is particularly important in controlling the activity of ras genes during embryogenesis, (Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, Labourier E, Reinert KL, Brown D, and Slack FJ, (2005), “RAS is regulated by the let-7 microRNA family”, Cell 120: 635–647). It has now been shown that let-7 RNA binds to known embryonic oncogenes, and by such binding, inactivates such oncogenes within adult cells, (Mayr C, Hemann MT, and Bartel DP, (2007), "Disrupting the Pairing Between let-7 and Hmga2 Enhances Oncogenic Transformation", Science, 315: 1576-1579). A simple hypothesis postulates that specific embryonic cell enhancers can have either positive or negative effects on their target embryonic genes within specific adult cells, progressively disrupting the adult gene signaling systems.  This allows oncogenesis to initiate from as little as one normal embryonic gene abnormally re-expressing itself within one adult normal cell. (4), (5), (6).

1. Takamizawa J, Konishi H, Yanagisawa K, Tomida S, Osada H, Endoh H, Harano T, Yatabe Y, Nagino M, Nimura Y, Mitsudomi T,  and Takahashi T, “Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival”, Cancer Res. 64: 3753–3756 (2004).

2. Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, Labourier E, Reinert KL, Brown D, and Slack FJ, “RAS is regulated by the let-7 microRNA family”, Cell 120: 635–647 (2005).

3. Mayr C, Hemann MT, and Bartel DP, "Disrupting the Pairing Between let-7 and Hmga2 Enhances Oncogenic Transformation", Science, 315: 1576-1579 (2007).

4. Additional References:

Published: Nature 448, 313-317 (19 July 2007).
doi:10.1038/nature05934;
http://www.nature.com/nature/journal/v448/n7151/abs/nature05934.html

"Generation of germline-competent induced pluripotent stem cells".
Okita K ¹, Ichisaka T ^{1, 2}, Yamanaka S ^{1, 2}

¹ Department of Stem Cell Biology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
² CREST, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan

Correspondence to: Shinya Yamanaka ^{1, 2}  (Email: yamanaka@frontier.kyoto-u.ac.jp).

We have previously shown that pluripotent stem cells can be induced from mouse fibroblasts by retroviral introduction of Oct3/4 (also called Pou5f1), Sox2, c-Myc and Klf4, and subsequent selection for Fbx15 (also called Fbxo15) expression. These induced pluripotent stem (iPS) cells (hereafter called Fbx15 iPS cells) are similar to embryonic stem (ES) cells in morphology, proliferation and teratoma formation; however, they are different with regards to gene expression and DNA methylation patterns, and fail to produce adult chimaeras. Here we show that selection for Nanog expression results in germline-competent iPS cells with increased ES-cell-like gene expression and DNA methylation patterns compared with Fbx15 iPS cells. The four transgenes (Oct3/4, Sox2, c-myc and Klf4) were strongly silenced in Nanog iPS cells. We obtained adult chimaeras from seven Nanog iPS cell clones, with one clone being transmitted through the germ line to the next generation. Approximately 20% of the offspring developed tumours attributable to reactivation of the c-myc transgene. Thus, iPS cells competent for germline chimaeras can be obtained from fibroblasts, but retroviral introduction of c-Myc should be avoided for clinical application.

Supplementary Information:
http://www.nature.com/nature/journal/v448/n7151/suppinfo/nature05934.html

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"Ultrastructural Probes of Active DNA Sites, and the RNA Activators of DNA". (PowerPoint Presentation).