Geroconversion: irreversible step to cellular senescence

Blagosklonny, Mikhail V.

doi:10.4161/15384101.2014.985507

Cited by 134 publications

(146 citation statements)

References 116 publications

(109 reference statements)

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“…41,42 Notably, oncogenes that engage OIS simultaneously induce cell cycle inhibitors, such as p16 and p21, while activating strong mitogenic signals, such as the MAPK and PI3K-AKT pathways; and as a result, initiate 2 processes involved in the senescence program: cell cycle arrest and geroconversion. 35,37,69 It was postulated that OIS prevents incipient cancer cells harboring oncogenic mutations from becoming fully tumorigenic. Our study asked the intriguing question: can OIS be engaged by persistent hyperactivation of an oncogene (STAT3), elicited by inappropriate, paracrine activation by extrinsic factors rather than intrinsic genetic changes?…”

Section: Discussionmentioning

confidence: 99%

“…19 In order to bypass the senescence program, developing cancer cells must dismantle cell cycle control by either inhibiting p16, pRb, and p53 or activating MYC (c-MYC). 35,37 Central to the senescence program that is engaged following either oncogenic RAS expression or persistent OSM/STAT3 activation is the repression of endogenous MYC (c-myc) expression. 19 Therefore, cell cycle arrest and geroconversion to irreversible senescence that is mediated by either oncogenic RAS or persistent OSM/STAT3 signaling can be abrogated simply by preventing MYC repression.…”

Section: Discussionmentioning

confidence: 99%

“…13,[19][20][21][26][27][28][29][30][31][32][33][34] Senescence is an irreversible, proliferationinhibiting response that occurs in 2 steps: 1) reversible cell cycle arrest followed by 2) futile growth-induced gerogenic conversion, or geroconversion. [35][36][37] Moreover, senescence is a major tumorsuppressive mechanism that acts as an early barrier to thwart cancer development. The presence of senescent cells in benign lesions, but not advanced malignant tumors, suggests that senescence barriers must be dismantled during oncogenic progression.…”

Section: Introductionmentioning

confidence: 99%

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STAT3-mediated SMAD3 activation underlies Oncostatin M-induced Senescence

et al. 2017

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Cytokines in the developing tumor microenvironment (TME) can drive transformation and subsequent progression toward metastasis. Elevated levels of the Interleukin-6 (IL-6) family cytokine Oncostatin M (OSM) in the breast TME correlate with aggressive, metastatic cancers, increased tumor recurrence, and poor patient prognosis. Paradoxically, OSM engages a tumor-suppressive, Signal Transducer and Activator of Transcription 3 (STAT3)-dependent senescence response in normal and non-transformed human mammary epithelial cells (HMEC). Here, we identify a novel link between OSM-activated STAT3 signaling and the Transforming Growth Factor-b (TGF-b) signaling pathway that engages senescence in HMEC. Inhibition of functional TGF-b/SMAD signaling by expressing a dominant-negative TGF-b receptor, treating with a TGF-b receptor inhibitor, or suppressing SMAD3 expression using a SMAD3-shRNA prevented OSMinduced senescence. OSM promoted a protein complex involving activated-STAT3 and SMAD3, induced the nuclear localization of SMAD3, and enhanced SMAD3-mediated transcription responsible for senescence. In contrast, expression of MYC (c-MYC) from a constitutive promoter abrogated senescence and strikingly, cooperated with OSM to promote a transformed phenotype, epithelial-mesenchymal transition (EMT), and invasiveness. Our findings suggest that a novel STAT3/SMAD3-signaling axis is required for OSM-mediated senescence that is coopted during the transformation process to confer aggressive cancer cell properties. Understanding how developing cancer cells bypass OSM/STAT3/SMAD3-mediated senescence may help identify novel targets for future "pro-senescence" therapies aiming to reengage this hidden tumor-suppressive response.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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STAT3-mediated SMAD3 activation underlies Oncostatin M-induced Senescence

et al. 2017

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“…50,[71][72][73] It is also unknown whether our mutant would be incapable of senescence, since it cannot arrest, and future work will look into these capabilities. 74,75 Data with the 2KQ-p53 mutants point to some exciting possibilities. First, there may be additional p53 transcriptional targets required for G1 arrest along with, or completely separate to p21.…”

Section: Discussionmentioning

confidence: 99%

Lysines in the tetramerization domain of p53 selectively modulate G1 arrest

Beckerman¹,

Yoh

Mattia-Sansobrino³

et al. 2016

Cell Cycle

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Functional in a tetrameric state, the protein product of the p53 tumor suppressor gene confers its tumorsuppressive activity by transactivating genes which promote cell-cycle arrest, senescence, or programmed cell death. How p53 distinguishes between these divergent outcomes is still a matter of considerable interest. Here we discuss the impact of 2 mutations in the tetramerization domain that confer unique properties onto p53. By changing lysines 351 and 357 to arginine, thereby blocking all post-translational modifications of these residues, DNA binding and transcriptional regulation by p53 remain virtually unchanged. On the other hand, by changing these lysines to glutamine (2KQ-p53), thereby neutralizing their positive charge and potentially mimicking acetylation, p53 is impaired in the induction of cell cycle arrest and yet can still effectively induce cell death. Surprisingly, when 2KQ-p53 is expressed at high levels in H1299 cells, it can bind to and transactivate numerous p53 target genes including p21, but not others such as miR-34a and cyclin G1 to the same extent as wild-type p53. Our findings show that strong induction of p21 is not sufficient to block H1299 cells in G1, and imply that modification of one or both of the lysines within the tetramerization domain may serve as a mechanism to shunt p53 from inducing cell cycle arrest.

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“…When cell cycle is arrested, the growth signal (if it cannot reactivate cycling) drives senescence. It was shown that inhibition of mTOR precludes senescence (by inhibiting the so called geroconversion) and causes reversible quiescence [26][27][28][29] . These data are in accord with our previous observation that isolated breast cancer cells, residually left behind after surgery and Temsirolimus treatment in mice, are quiescent for a certain time and eventually re-grow, resulting in tumor recurrence [9].…”

Section: Discussionmentioning

confidence: 99%