PMID- 22964580
OWN - NLM
STAT- MEDLINE
DCOM- 20121231
LR  - 20141120
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Linking)
VI  - 72
IP  - 21
DP  - 2012 Nov 1
TI  - Multiple roles of p53-related pathways in somatic cell reprogramming and stem 
      cell differentiation.
PG  - 5635-45
LID - 10.1158/0008-5472.CAN-12-1451 [doi]
AB  - The inactivation of p53 functions enhances the efficiency and decreases the 
      latency of producing induced pluripotent stem cells (iPSC) in culture. The 
      formation of iPSCs in culture starts with a rapid set of cell divisions followed 
      by an epigenetic reprogramming of the DNA and chromatin. The mechanisms by which 
      the p53 protein inhibits the formation of iPSCs are largely unknown. Using a 
      temperature sensitive mutant of the p53 (Trp53) gene, we examined the impact of 
      the temporal expression of wild type p53 in preventing stem cell induction from 
      somatic cells. We also explored how different p53 mutant alleles affect the 
      reprogramming process. We found that little or no p53 activity favors the entire 
      process of somatic cell reprogramming. Reactivation of p53 at any time point 
      during the reprogramming process not only interrupted the formation of iPSCs, but 
      also induced newly formed stem cells to differentiate. Among p53-regulated genes, 
      p21 (Cdkn1a), but not Puma (Bbc3) played a partial role in iPSCs formation 
      probably by slowing cell division. Activation of p53 functions in iPSCs induced 
      senescence and differentiation in stem cell populations. High rate of birth 
      defects and increases in DNA methylation at the IGF2-H19 loci in female offspring 
      of p53 knockout mice suggested that the absence of p53 may give rise to 
      epigenetic instability in a stochastic fashion. Consistently, selected p53 
      missense mutations showed differential effects on the stem cell reprogramming 
      efficiency in a c-Myc dependent manner. The absence of p53 activity and functions 
      also contributed to an enhanced efficiency of iPSC production from cancer cells. 
      The production of iPSCs in culture from normal and cancer cells, although 
      different from each other in several ways, both responded to the inhibition of 
      reprogramming by the p53 protein.
CI  - (c)2012 AACR.
FAU - Yi, Lan
AU  - Yi L
AD  - The Cancer Institute of New Jersey, Institute for Advanced Study, Princeton, New 
      Jersey 08540, USA.
FAU - Lu, Chiwei
AU  - Lu C
FAU - Hu, Wenwei
AU  - Hu W
FAU - Sun, Yvonne
AU  - Sun Y
FAU - Levine, Arnold J
AU  - Levine AJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120910
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Tumor Suppressor Protein p53)
SB  - IM
MH  - Animals
MH  - Cell Differentiation/*genetics
MH  - Cellular Reprogramming/*genetics
MH  - Epigenesis, Genetic/*genetics
MH  - Fluorescent Antibody Technique
MH  - HCT116 Cells
MH  - Humans
MH  - Induced Pluripotent Stem Cells/*cytology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Signal Transduction/physiology
MH  - Tumor Suppressor Protein p53/genetics/*metabolism
EDAT- 2012/09/12 06:00
MHDA- 2013/01/01 06:00
CRDT- 2012/09/12 06:00
PHST- 2012/09/12 06:00 [entrez]
PHST- 2012/09/12 06:00 [pubmed]
PHST- 2013/01/01 06:00 [medline]
AID - 0008-5472.CAN-12-1451 [pii]
AID - 10.1158/0008-5472.CAN-12-1451 [doi]
PST - ppublish
SO  - Cancer Res. 2012 Nov 1;72(21):5635-45. doi: 10.1158/0008-5472.CAN-12-1451. Epub 
      2012 Sep 10.