Unifying the p73 knockout phenotypes: TAp73 orchestrates multiciliogenesis

Napoli, Marco; Flores, Elsa R.

doi:10.1101/gad.283663.116

Cited by 8 publications

(5 citation statements)

References 9 publications

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“…The p73 knockout mice show abnormal lipid accumulation in the liver because of impaired triglyceride hydrolysis, with in vitro data pointing at an involvement of TAp73 in such a process (He et al , 2013, 2015). It would be interesting to assess the in vivo role of each p73 isoform, namely TAp73 and ΔNp73, in lipid metabolism in the respective isoform-specific knockout mice, even though a possible lack of evidence could be in line with some of the distinctive functions of these isoforms compared with the rest of their family (Napoli and Flores, 2016). …”

Section: Lipid Metabolism Control By the P53 Familymentioning

confidence: 99%

The p53 family orchestrates the regulation of metabolism: physiological regulation and implications for cancer therapy

Napoli

Flores

2016

Br J Cancer

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The p53 family of transcription factors is essential to counteract tumour formation and progression. Although previously this was exclusively associated with the ability of the p53 family to induce cell cycle arrest and apoptosis, an increasing number of reports have now indisputably demonstrated that the tumour suppressive functions of the p53 family members also rely on their ability to control and regulate cellular metabolism and maintain cellular oxidative homeostasis. Here, we review how each p53 family member, including p63 and p73, controls metabolic pathways in physiological conditions, and how these mechanisms could be exploited to provide anticancer therapeutic opportunities.

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Section: Lipid Metabolism Control By the P53 Familymentioning

confidence: 99%

The p53 family orchestrates the regulation of metabolism: physiological regulation and implications for cancer therapy

Napoli

Flores

2016

Br J Cancer

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“…2F, S2C). Trp73 encodes TP73, which triggers a downstream cascade towards multiciliated cell differentiation, including FOXJ1 (Napoli and Flores, 2016;Nemajerova et al, 2016), and key downstream TP73 targets (Cdkn1a, Myb, Foxj1, Ank3 and Six3) were all upregulated in our dataset (Fig. 2F).…”

Section: Mitochondrial Dysfunction In Astrocytes Induces Expression Of Motile Cilia Componentsmentioning

confidence: 90%

Mitochondrial dysfunction compromises ciliary homeostasis in astrocytes

Ignatenko

Malinen

Vihinen

et al. 2021

Preprint

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Reactive astrogliosis is a key component of neurological diseases. However, the active roles of astrocytes in pathogenic mechanisms and the involved molecular pathways are insufficiently understood. Here, we show that mitochondrial DNA depletion in astrocytes, causing mitochondrial spongiotic encephalopathy in mice, challenges the maintenance of primary cilium, the major cellular sensory organelle, which relays external signals to intracellular pathways. We show that mitochondrial respiratory chain deficiency in astrocytes induces FOXJ1 and RFX transcription factors, the master regulators of motile ciliogenesis, and consequently an aberrant nuclear expression program of motile cilia components. While the astrocytes still retain their single primary cilia, these organelles elongate and become remarkably distorted. Yet, respiratory chain deficiency in multiciliated ependymal cells does not cause overt cilia morphology defects. Collectively, our evidence points to an active signaling axis between astrocyte mitochondria and primary cilia. Furthermore, our data introduce metabolic ciliopathy as a pathomechanism for mitochondria-related neurodegenerative diseases.

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“…Studies from in vitro and in vivo models have shown that p73 has a broad range of functions in development, differentiation, reproduction, metabolic processes, genomic repair, senescence, angiogenesis, and tumor suppression [ 8 , 9 , 10 ]. For example, mice deficient in all p73 isoforms are runty and exhibit defects in neural development and multiciliogenesis [ 4 , 11 , 12 ]. Similarly, mice deficient in ΔNp73 isoforms are prone to delayed onset of moderate neurodegeneration [ 13 , 14 ] but do not develop tumors.…”

Section: Introductionmentioning

confidence: 99%

Small Proline-Rich Protein 2A and 2D Are Regulated by the RBM38-p73 Axis and Associated with p73-Dependent Suppression of Chronic Inflammation

Kong

Wang

Sun

et al. 2021

Cancers

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Small proline-rich protein 2A and 2D (SPRR2A and SPRR2D) provide barrier function in terminally differentiated stratified squamous epithelia through the epidermal differentiation complex. However, little is known how SPRR2A/2D expression is controlled and their role in chronic inflammation. Here, we showed that that SPRR2A/2D expression is controlled by a regulatory loop formed by RNA-binding protein RBM38 and tumor suppressor p73. Specifically, we found that SPRR2A/2D expression was induced by ectopic expression of RBM38 or p73 but suppressed by knockout of Rbm38 or p73. We also found that RBM38-mediated expression of SPRR2A/2D was p73-dependent and that induction of SPRR2A/2D during keratinocyte differentiation was dependent on both p73 and Rbm38. Additionally, we found that SPRR2A/2D expression was closely associated with p73 expression in normal and cancerous tissues. To determine the biological function of the RBM38-p73 loop potentially via SPRR2A/2D, we generated a cohort of wild-type, Rbm38−/−, Trp73+/−, and Rbm38−/−;Trp73+/− mice. We found that Rbm38−/−;Trp73+/− mice had a much shorter lifespan than that for Rbm38−/−—and to a lesser extent for Trp73+/− mice—but were less prone to spontaneous tumors than Trp73+/− or Rbm38−/− mice. We also found that Rbm38−/−;Trp73+/− mice exhibited weak expression of SPRR2A/2D in multiple tissues and were susceptible to systemic chronic inflammation, suggesting that decreased SPRR2A/2D expression is likely responsible for chronic inflammation in Rbm38−/−;Trp73+/− mice, leading to a shortened lifespan. Together, our data reveal that SPRR2A/2D are novel targets of the RBM38-p73 loop and contribute to p73-dependent suppression of chronic inflammation.

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Unifying the p73 knockout phenotypes: TAp73 orchestrates multiciliogenesis

Cited by 8 publications

References 9 publications

The p53 family orchestrates the regulation of metabolism: physiological regulation and implications for cancer therapy

The p53 family orchestrates the regulation of metabolism: physiological regulation and implications for cancer therapy

Mitochondrial dysfunction compromises ciliary homeostasis in astrocytes

Small Proline-Rich Protein 2A and 2D Are Regulated by the RBM38-p73 Axis and Associated with p73-Dependent Suppression of Chronic Inflammation

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