p53 has functional roles in tumor suppression as a guardian of the genome, surveillant of oncogenic cell transformation, and as recently demonstrated, a regulator of intracellular metabolism. Accumulating evidence has shown that the tumor microenvironment, accompanied by inflammation and tissue remodeling, is important for cancer proliferation, metastasis, and maintenance of cancer stem cells (CSCs) that self-renew and generate the diverse cells comprising the tumor. Furthermore, p53 has been demonstrated to inhibit inflammatory responses, and functional loss of p53 causes excessive inflammatory reactions. Moreover, the generation and maintenance of CSCs are supported by the inflammatory tumor microenvironment. Considering that the functions of p53 inhibit reprogramming of somatic cells to stem cells, p53 may have a major role in the inflammatory microenvironment as a tumor suppressor. Here, we review our current understanding of the mechanisms underlying the roles of p53 in regulation of the inflammatory microenvironment, tumor microenvironment, and tumor suppression.

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to protect the audiosensory organ from tissue damage from the immune system, the inner ear is separated from the circulating immune system by the blood-labyrinth barrier, which was previously considered an immune-privileged site. Recent studies have shown that macrophages are distributed in the cochlea, especially in the spiral ligament, spiral ganglion, and stria vascularis; however, the direct pathogen defence mechanism used by audiosensory receptor hair cells (Hcs) has remained obscure. Here, we show that Hcs are protected from pathogens by surrounding accessory supporting cells (Scs) and greater epithelial ridge (GeR or Kölliker's organ) cells (GeRcs). in isolated murine cochlear sensory epithelium, we established theiler's murine encephalomyelitis virus, which infected the Scs and GeRcs, but very few Hcs. the virus-infected Scs produced interferon (ifn)-α/β, and the viruses efficiently infected the Hcs in the ifn-α/β receptor-null sensory epithelium. interestingly, the virus-infected Scs and GeRcs expressed macrophage marker proteins and were eliminated from the cell layer by cell detachment. Moreover, lipopolysaccharide induced phagocytosis of the Scs without cell detachment, and the Scs phagocytosed the bacteria. these results reveal that Scs function as macrophage-like cells, protect adjacent Hcs from pathogens, and provide a novel anti-infection inner ear immune system.The inner ear was previously regarded as an immune-privileged site because the blood-labyrinthine barrier prevents the peripheral immune system accessing this site 1 . To minimize any collateral tissue damage induced by an immune reaction, delicate tissues, such as those of the central nervous system (CNS), sensory organs (eyes and ears) and gonads (testes and ovaries), are separated from the peripheral blood by a physical barrier 2 . In the mammalian inner ear, audiosensory receptor hair cells (HCs) are located over the basilar membrane in the organ of Corti, which vibrates in response to sound waves 3 . This sensory organ lies in the cochlear duct (known as the scala media) and is separated from the vestibular duct and the tympanic duct by the avascular Reissner's membrane and a basilar membrane, respectively 4 . To offset the constant auditory sensation of heartbeats, the direct blood supply to the organ of Corti is sparse. The oxygen supply to HCs is provided by the dense capillary network of the stria vascularis, which is present in the lateral wall of the cochlear duct, constitutes the major feeding vessels 1,5 .HCs transduce the mechanical force generated by sound waves into electrical signals 6 and are aligned in four rows, one of which, the inner HCs (IHCs) detect sound, while the other three rows of outer HCs (OHCs) have amplitude and frequency-resolving capabilities 3,6 . OHCs are surrounded by supporting cells (SCs), termed Hensen's cells and Claudius' cells 3 . IHCs are surrounded by greater epithelial ridge (GER or Kölliker's organ) cells (GERCs) in the immature neonatal inner ear, which develop later on into mature SCs and a...

Tumor suppressor p53 plays an integral role in DNA-damage induced apoptosis, a biological process that protects against tumor progression. Cell shape dramatically changes when cells undergo apoptosis, which is associated with actomyosin contraction; however, it remains entirely elusive how p53 regulates actomyosin contraction in response to DNA-damaging agents. To identify a novel p53 regulating gene encoding the modulator of myosin, we conducted DNA microarray analysis. We found that, in response to DNA-damaging agent doxorubicin, expression of myotonic dystrophy protein kinase (DMPK), which is known to upregulate actomyosin contraction, was increased in a p53-dependent manner. The promoter region of DMPK gene contained potential p53-binding sequences and its promoter activity was increased by overexpression of the p53 family protein p73, but, unexpectedly, not of p53. Furthermore, we found that doxorubicin treatment induced p73 expression, which was significantly attenuated by downregulation of p53. These data suggest that p53 induces expression of DMPK through upregulating p73 expression. Overexpression of DMPK promotes contraction of the actomyosin cortex, which leads to formation of membrane blebs, loss of cell adhesion, and concomitant caspase activation. Taken together, our results suggest the existence of p53-p73-DMPK axis which mediates DNA-damage induced actomyosin contraction at the cortex and concomitant cell death.