p53 plays a central role in lymphatic anomalies
Mylavarapu, R.; Kulikauskas, M.; Dierkes, C.; Finlon, J.; Sobhani, N.; Stevens, W.; Mangette, M.; Arbab, F.; Box, N. F.; Muley, A.; Shawber, C.; Lovell, M.; Kiefer, F.; Tamburini, B.; Terzian, T.
Show abstract
Activation of the transcription factor p53 has been associated with several developmental syndromes. In normal tissues, p53 is kept at very low undetectable physiological levels. When triggered by cellular stressors, p53 prompts important anti-proliferative and apoptotic programs part of its tumor suppressor activity or as the guardian of tissue homeostasis. We generated two murine models that display cutaneous hemorrhaging, severe edema, and distended blood-filled lymphatic vessels at late-gestation due to overactive p53 uniquely affecting lymphatic endothelial cells during development. Overactive p53 operated distinctively through anti-proliferative route in this tissue resulting in a decrease in initial lymphatics that normally absorb interstitial fluid. Remarkably, genetic or pharmacologic normalization of p53 restored lymphatic homeostasis and reversed lymphatic phenotypes. In parallel, several human lymphatic disease tissues exhibited high p53 levels exclusively in the lymphatic endothelium while p53 remained undetectable in surrounding arterial or venous vessels. We report here, for the first time, an extended role that the p53 pathway plays in the genesis of lymphatic homeostasis deficiencies opening the way for new therapeutic avenues for these rare, poorly understood, and incurable lymphatic maladies.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
Similar papers in this journal
- Claudin5 protects the peripheral endothelial barrier in an organ and vessel type-specific manner 95%
- Touch receptor end-organ innervation and function requires sensory expression of the transcription factor Meis2 94%
- svep1 and tie1 genetically interact and affect aspects of facial lymphatic development in a Vegfc-independent manner 93%
Similar papers in this journal
- AP-2α/AP-2β transcription factors are key regulators of epidermal homeostasis 94%
- Epidermal loss of PRMT5 leads to the emergence of an atypical basal keratinocyte-like cell population and defective skin stratification 94%
- UBE2N is essential for maintenance of skin homeostasis and suppression of inflammation 93%