p53: Guardian of the genome is also a suppressor of cell invasion?

Mukhopadhyay, Utpal K.; Mak, Alan S.

doi:10.4161/cc.8.16.9269

Cited by 14 publications

(9 citation statements)

References 8 publications

(8 reference statements)

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“…In culture, aortic VSMC from ApoE -/- /p53 -/- mice produce significantly more podosomes and are more invasive (Fig 5B and 5C), consistent with previous reports from us [3,5,6,10,11]. In those previous studies, we have identified p53 as a suppressor of Src-induced podosome formation and proposed that p53 acts by upregulating the expression of two anti-invasion regulators: caldesmon, an actin-binding protein and a negative regulator of podosome assembly [10], and PTEN that inhibits the Src-mediated PI3K-Akt and Stat3 pro-invasion pathways [11,32].…”

Section: Discussionsupporting

confidence: 92%

“…We have shown in vitro that p53 also acts as a suppressor of cell migration and invasion in VSMC by down regulating the formation of circular dorsal ruffles (CDR) and podosomes [3,5,6,10,11]. A number of studies have been attempted to explore the anti-proliferative and pro-apoptotic roles of p53 in atherosclerosis using genetically engineered mouse models [12–20].…”

Section: Introductionmentioning

confidence: 99%

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Effects of p53-knockout in vascular smooth muscle cells on atherosclerosis in mice

et al. 2017

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In vitro and in vivo evidence has indicated that the tumor suppressor, p53, may play a significant role in the regulation of atherosclerotic plaque formation. In vivo studies using global knockout mice models, however, have generated inconclusive results that do not address the roles of p53 in various cell types involved in atherosclerosis. In this study, we have specifically ablated p53 in vascular smooth muscle cells (VSMC) in the ApoE-/- mouse model to investigate the roles of p53 in VSMC in atherosclerotic plaque formation and stability. We found that p53 deficiency in VSMC alone did not affect the overall size of atherosclerotic lesions. However, there was a significant increase in the number of p53-/- VSMC in the fibrous caps of atherosclerotic plaques in the early stages of plaque development. Loss of p53 results in migration of VSMC at a faster rate using wound healing assays and augments PDGF-induced formation of circular dorsal ruffles (CDR), known to be involved in cell migration and internalization of surface receptors. Furthermore, aortic VSMC from ApoE-/- /p53-/- mice produce significantly more podosomes and are more invasive. We conclude that p53-/- VSMC are enriched in the fibrous caps of lesions at early stages of plaque formation, which is caused in part by an increase in VSMC migration and invasion as shown by p53-/- VSMC in culture having significantly higher rates of migration and producing more CDRs and invasive podosomes.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Effects of p53-knockout in vascular smooth muscle cells on atherosclerosis in mice

et al. 2017

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“…Our previous work has shown that Src-induced formation of podosome rosettes in RASM cells and invasion of ECM are also down regulated by p53 involving PTEN, Akt and caldesmon [18], [19], [23], [26]. It is likely that p53 may act on multiple effectors of cytoskeleton remodeling in a concerted manner to down regulate cell migration and invasion.…”

Section: Discussionmentioning

confidence: 99%

p53 Down Regulates PDGF-Induced Formation of Circular Dorsal Ruffles in Rat Aortic Smooth Muscle Cells

et al. 2014

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The tumor suppressor, p53, negatively regulates cell migration and invasion in addition to its role in apoptosis, cell cycle regulation and senescence. Here, we study the roles of p53 in PDGF-induced circular dorsal ruffle (CDR) formation in rat aortic smooth muscle (RASM) cells. In primary and immortalized RASM cells, up-regulation of p53 expression or increase in activity with doxorubicin inhibits CDR formation. In contrast, shRNA-knockdown of p53 or inhibition of its activity with pifithrin α promotes CDR formation. p53 acts by up-regulating PTEN expression, which antagonizes Rac and Cdc42 activation. Both lipid and protein phosphatase activities of PTEN are required for maximal suppression of CDR, but the lipid activity clearly plays the dominant role. N-WASP, the downstream effector of Cdc42, is the major positive contributor to CDR formation in RASM, and is an indirect target of p53. The Rac effector, WAVE2, appears to also play a minor role, while WAVE1 has no significant effect in CDR formation. In sum, we propose that p53 suppresses PDGF-induced CDR formation in RASM cells by upregulating PTEN leading mainly to the inhibition of the Cdc42-N-WASP pathway.

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“…7 Together, these observations suggest that there is a positive feedback loop that regulates the expression and stability of p53 and PTEN. signaling pathways involving cell migration and cytoskeleton regulators (RhoGTPases, integrins, N-WASP, Arp2/3, AFAP, caldesmon and cortactin), 44 48 and tumor suppressors (p53, PTEN), 5,6 and undoubtedly others yet to be discovered.…”

Section: Podosomes and Vascular Smooth Muscle Cell Invasionmentioning

confidence: 99%

p53: Guardian of the genome is also a suppressor of cell invasion?

Cited by 14 publications

References 8 publications

Effects of p53-knockout in vascular smooth muscle cells on atherosclerosis in mice

Effects of p53-knockout in vascular smooth muscle cells on atherosclerosis in mice

p53 Down Regulates PDGF-Induced Formation of Circular Dorsal Ruffles in Rat Aortic Smooth Muscle Cells

p53 regulation of podosome formation and cellular invasion in vascular smooth muscle cells

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