Dual inactivation of Hus1 and p53 in the mouse mammary gland results in accumulation of damaged cells and impaired tissue regeneration

Yazinski, Stephanie A.; Westcott, Peter M.K.; Ong, Kelly; Pinkas, Jan; Peters, Rachel M.; Weiss, Robert S.

doi:10.1073/pnas.0904965106

Cited by 14 publications

(16 citation statements)

References 48 publications

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“…6 The massive expansion of the ductal tree in mouse mammary tumor virus-Neu mammary tissue upon p38α/β inhibition indicates that p38α/β acts to restrain HER2/neu signaling through ATF-2 activation 99 and probably by p53 induction. 101–104 Taken together, p38α is critical for the development of hollow ducts during MG development, a function that may explain its crucial role as an early breast cancer suppressor (Figures 1 and 2). …”

Section: Perk and P38 As Novel Stress-activated Regulators Of Mammarymentioning

confidence: 96%

Stress signaling and the shaping of the mammary tissue in development and cancer

2014

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The postnatal mammary gland develops extensively through cycles of proliferation, branching, involution and remodeling. We review recent advances made in the field of stress signaling pathways and its roles in mammary gland organogenesis, how they contribute to normal organ specification and homeostasis and how its subversion by oncogenes leads to cancer. We analyze stress signaling in mammary gland biology taking into account the interrelationship with the extracellular matrix and adhesion signaling during morphogenesis. By integrating the information gathered from in vivo and three dimensional in vitro organogenesis studies, we review the novel contribution of p38SAPK, c-Jun NH2-terminal kinase and PKR-like endoplasmic reticulum kinase (PERK) signaling pathways to the timely activation of cell death, correct establishment of polarity and growth arrest and autophagy, respectively. We also review the evidence supporting that the activation of the aforementioned stress kinases maintain breast acinar structures as part of a tumor suppressive program and that its deregulation is commonplace during breast cancer initiation.

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Section: Perk and P38 As Novel Stress-activated Regulators Of Mammarymentioning

confidence: 96%

Stress signaling and the shaping of the mammary tissue in development and cancer

2014

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“…It was shown that p53 is an important component in the renewal of adult tissues that have "increased genomic instability phenotypes." 18,34,38 The activity of p53 is thought to be involved in clearing out cells that have accumulated DNA damage. This results in the induction of senescence and immune-mediated clearance.…”

Section: Epimorphic Regeneration In Mice Is P53-independentmentioning

confidence: 99%

Epimorphic regeneration in mice is p53-independent

Arthur¹,

Demarest²,

Clark³

et al. 2010

Cell Cycle

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T he process of regeneration is most readily studied in species of sponge, hydra, planarian and salamander (i.e., newt and axolotl). The closure of MRL mouse ear pinna through-and-through holes provides a mammalian model of unusual wound healing/regeneration in which a blastema-like structure closes the ear hole and cartilage and hair follicles are replaced. Recent studies, based on a broad level of DNA damage and a cell cycle pattern of G 2 /M "arrest," showed that p21Cip1/Waf1 was missing from the MRL mouse ear and that a p21-null mouse could close its ear holes. Given the p53/p21 axis of control of DNA damage, cell cycle arrest, apoptosis and senescence, we tested the role of p53 in the ear hole regenerative response. Using backcross mice, we found that loss of p53 in MRL mice did not show reduced healing. Furthermore, cross sections of MRL. p53 -/-mouse ears at 6 weeks post-injury showed an increased level of adipocytes and chondrocytes in the region of healing whereas MRL or p21 -/-mice showed chondrogenesis alone in this same region, though at later time points. In addition, we also investigated other cell cyclerelated mutant mice to determine how p21 was being regulated. We demonstrate that p16 and Gadd45 null mice show little healing capacity. Interestingly, a partial healing phenotype in mice with a dual Tgfβ/Rag2 knockout mutation was seen. These data demonstrate an independence of p53 signaling for mouse appendage regeneration and suggest that the role of p21 in this process is possibly through the abrogation of the Tgfβ/Smad pathway.

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“…Interference with the ATR pathway in the absence of p53 sensitizes cultured cells to DNA-damaging agents and lethally disrupts tissue homeostasis in adult mice through the accumulation of highly damaged cells (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12). Notably, recent reports have shown that oncogene expression can induce DNA replication stress (13)(14)(15)(16)(17)(18)(19)(20)(21)(22) and, similarly to p53 deficiency, creates an increased reliance on the ATR pathway for genome maintenance during DNA synthesis and cell survival (23).…”

Section: Introductionmentioning

confidence: 99%

Oncogenic stress sensitizes murine cancers to hypomorphic suppression of ATR

Schoppy

Ragland²,

Gilad³

et al. 2012

J. Clin. Invest.

166

162

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Oncogenic Ras and p53 loss-of-function mutations are common in many advanced sporadic malignancies and together predict a limited responsiveness to conventional chemotherapy. Notably, studies in cultured cells have indicated that each of these genetic alterations creates a selective sensitivity to ataxia telangiectasia and Rad3-related (ATR) pathway inhibition. Here, we describe a genetic system to conditionally reduce ATR expression to 10% of normal levels in adult mice to compare the impact of this suppression on normal tissues and cancers in vivo. Hypomorphic suppression of ATR minimally affected normal bone marrow and intestinal homeostasis, indicating that this level of ATR expression was sufficient for highly proliferative adult tissues. In contrast, hypomorphic ATR reduction potently inhibited the growth of both p53-deficient fibrosarcomas expressing H-ras G12V and acute myeloid leukemias (AMLs) driven by MLL-ENL and N-ras G12D . Notably, DNA damage increased in a greater-than-additive fashion upon combining ATR suppression with oncogenic stress (H-ras G12V , K-ras G12D , or c-Myc overexpression), indicating that this cooperative genome-destabilizing interaction may contribute to tumor selectivity in vivo. This toxic interaction between ATR suppression and oncogenic stress occurred without regard to p53 status. These studies define a level of ATR pathway inhibition in which the growth of malignancies harboring oncogenic mutations can be suppressed with minimal impact on normal tissue homeostasis, highlighting ATR inhibition as a promising therapeutic strategy.

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Dual inactivation of Hus1 and p53 in the mouse mammary gland results in accumulation of damaged cells and impaired tissue regeneration

Cited by 14 publications

References 48 publications

Stress signaling and the shaping of the mammary tissue in development and cancer

Stress signaling and the shaping of the mammary tissue in development and cancer

Epimorphic regeneration in mice is p53-independent

Oncogenic stress sensitizes murine cancers to hypomorphic suppression of ATR

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