ASPL-TFE3 Oncoprotein Regulates Cell Cycle Progression and Induces Cellular Senescence by Up-Regulating p21

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ASPL-TFE3 Oncoprotein Regulates Cell Cycle Progression and Induces Cellular Senescence by Up-Regulating p21



Alveolar soft part sarcoma is an extremely rare soft tissue sarcoma with poor prognosis. It is characterized by the unbalanced recurrent chromosomal translocation der(17)t(X;17)(p11;q25), resulting in the generation of an ASPL-TFE3 fusion gene. ASPL-TFE3 oncoprotein functions as an aberrant transcriptional factor and is considered to play a crucial role in the tumorigenesis of alveolar soft part sarcoma. However, the underlying molecular mechanisms are poorly understood. In this study, we identified p21 (p21WAF1/CIP1) as a direct transcriptional target of ASPL-TFE3. Ectopic ASPL-TFE3 expression in 293 cells resulted in cell cycle arrest and significant increases in protein and mRNA levels of p21. ASPL-TFE3 activated p21 expression in a p53-independent manner through direct transcriptional interactions with the p21 promoter region. When ASPL-TFE3 was expressed in human bone marrow-derived mesenchymal stem cells in a tetracycline-inducible manner, we observed the up-regulation of p21 expression and the induction of senescence-associated β-galactosidase activity. Suppression of p21 significantly decreased the induction of ASPL-TFE3-mediated cellular senescence. Furthermore, ASPL-TFE3 expression in mesenchymal stem cells resulted in a significant up-regulation of proinflammatory cytokines associated with senescence-associated secretory phenotype (SASP). These results show that ASPL-TFE3 regulates cell cycle progression and induces cellular senescence by up-regulating p21 expression. In addition, our data suggest a potential mechanism by which ASPL-TFE3-induced senescence may play a role in tumorigenesis by inducing SASP, which could promote the protumorigenic microenvironment.


https://pubmed.ncbi.nlm.nih.gov/27673450/

When in the nucleus, p21 can act as a tumor suppressor: it may inhibit CKIs in G1 or G2/M cell cycle arrest initiated by p53; it may downregulate many, but not all, DNA repair pathways; it can limit the proliferation of stem cells; and it can also induce senescence [10].
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p21: A Two-Faced Genome Guardian

What is the Effect of P21 in Cellular Function?

https://www.news-medical.net/life-scien ... ction.aspx

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“P21 and cancer

All of p21’s roles in cellular function are related to its mediation of cancer. This is because p21 governs, at least in part, all vital cellular functions, all of which are implicated in the establishment, progression, and therapeutic response of cancerous cells.

Given that p21 has been implicated in cell cycle arrest it is unsurprising that scientists have exploited its function to treat cancer. Some chemotherapeutic agents have been designed to induce p21 activity to have the effect of inhibiting cancer progression.

P21 has an inhibitory effect on CDK2 activity, which, in turn, inhibits cell cycle progression. Through activating p21, and inhibiting CDK2, researchers have recognized the therapeutic potential of targeting p21 to prevent the proliferation of cancer cells.

Breast cancer, in particular, has been linked with p21’s impact on the regulation of gene transcription. The expression of the estrogen receptor-α (ERα)-dependent gene is mediated, at least in part, by p300–CREBBP-driven gene transcription, which is activated by p21.

Differentiation of ERα-positive cells is induced by this activity, and therefore, the upregulation of p21 can prevent the growth of ERα-positive breast cancer cells. This discovery has alerted scientists to the impact that p21 can have on the efficacies of anti-estrogen treatments.

One hallmark of cancer is its strong ability to avoid apoptosis, allowing cancer cells to thrive in spite of the body’s efforts to initiate regulated cell death processes.

P21 has been considered both a help and a hindrance in cancer progression, on one hand, it has been targeted to stimulate cell cycle arrest to inhibit cancer progression, but on the other, it has been associated with apoptosis inhibition, a condition that allows cancer to thrive. P21 can protect cells from apoptosis by promoting cell cycle inhibition, and cells that are not active are less likely to trigger apoptosis.

Conversely, p21’s role in DNA repair once again sees it in a helpful role to prevent cancer progression. Because p21 inhibits cell cycle progression as well as apoptosis, DNA repair can proceed during this pause in the cycle. DNA repair is vital to protecting against cancer, and therefore p21 may contribute to tumor-suppressing activities, although further research is needed to confirm this.”