التفاصيل البيبلوغرافية
| العنوان: |
Noncanonical NOTCH Signaling Limits Self-Renewal of Human Epithelial and Induced Pluripotent Stem Cells through ROCK Activation. |
| المؤلفون: |
Takashi Yugawa1, Koichiro Nishino2, Shin-ichi Ohno1, Tomomi Nakahara1, Masatoshi Fujita3, Naoki Goshima4, Akihiro Umezawa1,5, Tohru Kiyonoa1 tkiyono@ncc.go.jp |
| المصدر: |
Molecular & Cellular Biology. Nov2013, Vol. 33 Issue 21, p4434-4447. 14p. |
| مصطلحات موضوعية: |
*NOTCH proteins, *KERATINOCYTES, *CELL differentiation, *PLURIPOTENT stem cells, *RHO GTPases |
| مستخلص: |
NOTCH plays essential roles in cell fate specification during embryonic development and in adult tissue maintenance. In keratinocytes, it is a key inducer of differentiation. ROCK, an effector of the small GTPase Rho, is also implicated in keratinocyte differentiation, and its inhibition efficiently potentiates immortalization of human keratinocytes and greatly improves survival of dissociated human pluripotent stemcells. However, the molecular basis for ROCK activation is not fully established in these contexts. Here we provide evidence that intracellular forms of NOTCH1 trigger the immediate activation of ROCK1 independent of its transcriptional activity, promoting differentiation and resulting in decreased clonogenicity of normal human keratinocytes. Knockdown of NOTCH1 abrogated ROCK1 activation and conferred sustained clonogenicity upon differentiation stimuli. Treatment with a ROCK inhibitor, Y-27632, or ROCK1 silencing substantially rescued the growth defect induced by activated NOTCH1. Furthermore, we revealed that impaired self-renewal of human induced pluripotent stemcells upon dissociation is, at least in part, attributable to NOTCH-dependent ROCK activation. Thus, the present study unveils a novel NOTCH-ROCK pathway critical for cellular differentiation and loss of self-renewal capacity in a subset of immature cells. [ABSTRACT FROM AUTHOR] |
| قاعدة البيانات: |
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