Dwarfism, impaired skin development, skeletal muscle atrophy, delayed bone development, and impeded adipogenesis in mice lacking Akt1 and Akt2

Peng, Xiao; Xu, Pei; Chen, Mei Ling; Hahn-Windgassen, Annett; Skeen, Jennifer; Jacobs, Joel; Sundararajan, Deepa; Chen, William S.; Crawford, Susan E.; Coleman, Kevin; Hay, Nissim

doi:10.1101/gad.1089403

Cited by 737 publications

(708 citation statements)

References 66 publications

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“…Deletion of Akt1 causes thinner epidermal layers and the retarded hair follicle development . A more severe reduction in epidermal layers and hair follicles at birth was reported in Akt1 À/À Akt2 À/À and Akt1 À/À Akt3 þ /À mutant mice (Peng et al, 2003;Yang et al, 2005), suggesting redundant functions among Akt family members in the skin. More intriguingly, the keratinocyte-specific deletion of Pten resulted in epidermal hyperplasia and accelerated hair morphogenesis during the postnatal period Backman et al, 2004).…”

Section: Role Of Akt Signaling In Epidermal Stem Cells and Progenitorsmentioning

confidence: 82%

Akt activation induces epidermal hyperplasia and proliferation of epidermal progenitors

Murayama¹,

Kimura²,

Tarutani

et al. 2007

Oncogene

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Various common signaling pathways maintain tissue stem cells, including Notch and Wnt/b-catenin signals. Phosphoinositide-3 kinase (PI3K)/Akt signaling regulates the 'stemness' of several stem cells in culture, specifically in maintaining embryonic stem and neural stem cells, and in deriving embryonic germ cells from primordial germ cells. We examined the effect of Akt signaling in epidermal cells in transgenic mice expressing an Akt-Mer fusion protein whose kinase activity was conditionally activated by treatment with 4-hydroxytamoxifen (4OHT). The topical application of 4OHT to adult skin of the transgenic mice induced new hair growth in resting phase follicles. In addition, the mice showed hyperplasia in interfollicular epidermis (IFE) and hair follicles, which was presumably caused by the extensive proliferation of keratinocytes in basal layer of IFE and outer root sheath of hair follicles, respectively. The progenitor cell population increased consistently in 4OHT-treated transgenic mice. Our results show that PI3K/Akt signaling induces epidermal hyperplasia and proliferation of epidermal progenitors.

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Section: Role Of Akt Signaling In Epidermal Stem Cells and Progenitorsmentioning

confidence: 82%

Akt activation induces epidermal hyperplasia and proliferation of epidermal progenitors

Murayama¹,

Kimura²,

Tarutani

et al. 2007

Oncogene

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“…Work here might be complicated by redundant functions of the family members of Akt1/2/3 and Tcl1 gene family. However, it is interesting to observe that in the epidermis, deletion of Akt1 causes thinner epidermal layers and retarded-HF development, whereas double mutants (Akt1 À/À Akt2 À/À and Akt1 À/À Akt3 À/À ) (Peng et al, 2003;Yang et al, 2005) show more severe defects, and transgenic mice expressing Akt-Mer fusion proteins induces epidermal hyperplasia and proliferation of epidermal progenitors leading to epidermal and follicular hyperplasia (Murayama et al, 2007). As already pointed out before, Tcl1 is involved in the normal-self renewal of ES cells (Glover et al, 2006;Matoba et al, 2006;GalanCaritad et al, 2007) and upstream genes such as transcription factor Oct4, which directly activates Tcl1 in ES cells and is expressed in human HFs (Yu et al, 2006), should also be taken into account.…”

Section: Discussionmentioning

confidence: 99%

The Tcl1 oncogene defines secondary hair germ cells differentiation at catagen–telogen transition and affects stem-cell marker CD34 expression

et al. 2009

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Overexpression of the TCL1 gene family plays a role in the onset of T-cell leukemias in mice and in humans. The Tcl1 gene is tightly regulated during early embryogenesis in which it participates in embryonic stem (ES)-cells proliferation and during lymphoid differentiation. Here, we provide evidences that Tcl1 is also important in mouse hair follicle (HF) and skin homeostasis. We found that Tcl1 À/À adult mice exhibit hair loss, leading to alopecia with extensive skin lesions. By analysing Tcl1 expression in the wild-type (wt) skin through different stages of hair differentiation, we observe high levels in the secondary hair germ (HG) cells and hair bulges, during early anagen and catagen-telogen transition phases. The loss of Tcl1 does not result in apparent skin morphological defects during embryonic development and at birth, but its absence causes a reduction of proliferation in anagen HFs. Importantly, we show the that absence of Tcl1 induces a significant loss of the stem-cell marker CD34 (but not a6-integrin) expression in the bulge cells, which is necessary to maintain stem-cell characteristics. Therefore, our findings indicate that Tcl1 gene(s) might have important roles in hair formation, by its involvement in cycling and self-renewal of transient amplifying (TA) and stem-cell (SC) populations.

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“…In contrast, Akt2 null mice display defects in the regulation of blood glucose level 216 . Perhaps surprisingly, both Akt1 -/-and Akt2 -/-mice were viable, and even the double knockout Akt1/2 -/-mice developed normally through embryogenesis, suggesting the three isoforms can substitute for each other in cellular processes, at least during development 217 . In transgenic mice expressing constitutively activated Akt, increased resistance to apoptosis and increased tumour formation were observed 218 .…”

Section: The Akt Pathwaymentioning

confidence: 99%

Role of the pro-survival molecule Bfl-1 in melanoma

Hind

Carter

Harris

et al. 2015

The International Journal of Biochemistry & Cell Biology

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Melanoma, the cancer derived from the melanocytes of the skin, is becoming an ever more common cancer in the ageing population of the developed world and displays an intrinsic resistance to current therapies. This chemo resistance makes metastatic melanoma an extremely difficult cancer to treat leading to a 5 year survival rate of just 20%. As such, it is important to unearth new potential drug targets to increase the prospects for melanoma patients.Bfl-1 is a pro-survival protein of the Bcl-2 family of apoptosis regulating proteins. It has been found to be over-expressed in a small subset of chemo resistant tumours, including melanoma. Accordingly, I characterised the molecule in melanoma cells and determined its role in protecting these cells from chemotherapy-induced apoptosis. I elucidated the expression profile and half-lives of the protein and mRNA across a panel of melanoma cell-lines and healthy melanocytes. I also confirmed, using pathway specific inhibitors, that Bfl-1 was transcriptionally regulated by the NFB pathway and concluded through pulsechase experiments that Bfl-1 protein was degraded, at least in part, by the proteasome. Subcellular fractionation and indirect immunofluorescence techniques elucidated that Bfl-1 was located mostly at the mitochondria in both resting and apoptotic cells, with a diffuse level present throughout the cytoplasm. As well as characterising the protein in both melanoma cells and healthy primary melanocytes, I determined its role in the resistance of these cells to apoptosis. Over-expressed Bfl-1 was found to protect melanoma cells from apoptosis caused by a range of chemotherapeutic agents in A375 melanoma cells, which naturally expressed very low levels of Bfl-1. Further, knock down of Bfl-1 using siRNA technology in melanoma cells revealed the dependence of these cells on Bfl-1 for their resistance to certain chemotherapeutic agents currently used in melanoma treatment, including the MEK inhibitor PD901. All together, this research contributes to our understanding of Bfl-1 and highlights it as a potentially important therapeutic target in metastatic melanoma.

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Dwarfism, impaired skin development, skeletal muscle atrophy, delayed bone development, and impeded adipogenesis in mice lacking Akt1 and Akt2

Cited by 737 publications

References 66 publications

Akt activation induces epidermal hyperplasia and proliferation of epidermal progenitors

Akt activation induces epidermal hyperplasia and proliferation of epidermal progenitors

The Tcl1 oncogene defines secondary hair germ cells differentiation at catagen–telogen transition and affects stem-cell marker CD34 expression

Role of the pro-survival molecule Bfl-1 in melanoma

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