Direct promoter induction of p19Arf by Pit-1 explains the dependence receptor RET/Pit-1/p53-induced apoptosis in the pituitary somatotroph cells

Díaz‐Rodriguez, Esther; García-Lavandeira, Montserrat; Pérez-Romero, Sihara; Senra, Ana; Cañibano, Carmen; Palmero, Ignacio; Borrello, M. G.; Diéguez, Carlos; Álvarez, Clara V.

doi:10.1038/onc.2011.458

Cited by 21 publications

(52 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Recently, in the normal male pituitary gland, the existence of TUNEL-positive cells that coexpress Pit-1 (GH) and p19Arf has been demonstrated [95] (fig. 3d).…”

Section: Apoptosis and Its Equilibria With Stem Cell Recruitment In Tmentioning

confidence: 99%

“…For example, the Ret knockout causes pituitary hyperplasia at birth due to excess somatotroph numbers, while a retrovirus expressing Ret can prevent estrogen-induced hyperplasia [92]. The apoptotic pathway has a survival correlate when the ligand is present: GDNF prevents RET processing, inducing dimerization, tyrosine kinase activation and phosphorylation of intracellular proteins [92,95,96]. One of the activated survival pathways involves Akt, which represses Pit-1 expression to levels insufficient to initiate apoptosis and compatible with life and GH production.…”

Section: Apoptosis and Its Equilibria With Stem Cell Recruitment In Tmentioning

confidence: 99%

“…Once this complex is formed, caspase 3 is activated to aCasp3, which processes RET and PKCd, and this phosphorylates transcription factors such as CREB and cEBPa, leading to uncontrolled Pit-1 transcription [92,94]. Excess Pit-1 in turn induces p19Arf transcription, p53 accumulation and apoptosis [95]. …”

Section: Apoptosis and Its Equilibria With Stem Cell Recruitment In Tmentioning

confidence: 99%

“…Excess Pit-1 activates the Arf promoter (Pit-1+/p19Arf+, cyan merge). All these markers are nuclear (pink merge: TUNEL+Pit-1+p19Arf+DAPI) [95]. …”

Section: From Adult Stem To Committed and Differentiated Cells In The Apmentioning

confidence: 99%

See 3 more Smart Citations

Pituitary Cell Turnover: From Adult Stem Cell Recruitment through Differentiation to Death

et al. 2015

View full text Add to dashboard Cite

The recent demonstration using genetic tracing that in the adult pituitary stem cells are normally recruited from the niche in the marginal zone and differentiate into secretory cells in the adenopituitary has elegantly confirmed the proposal made when the pituitary stem cell niche was first discovered 5 years ago. Some of the early controversies have also been resolved. However, many questions remain, such as which are the markers that make a pituitary stem cell truly unique and the exact mechanisms that trigger recruitment from the niche. Little is known about the processes of commitment and differentiation once a stem cell has left the niche. Moreover, the acceptance that pituitary cells are renewed by stem cells implies the existence of regulated mechanisms of cell death in differentiated cells which must themselves be explained. The demonstration of an apoptotic pathway mediated by RET/caspase 3/Pit-1/Arf/p53 in normal somatotrophs is therefore an important step towards understanding how pituitary cell number is regulated. Further work will elucidate how the rates of the three processes of cell renewal, differentiation and apoptosis are balanced in tissue homeostasis after birth, but altered in pituitary hyperplasia in response to physiological stimuli such as puberty and lactation. Thus, we can aim to understand the mechanisms underlying human disease due to insufficient (hypopituitarism) or excess (pituitary tumor) cell numbers.

show abstract

“…Recently, in the normal male pituitary gland, the existence of TUNEL-positive cells that coexpress Pit-1 (GH) and p19Arf has been demonstrated [95] (fig. 3d).…”

Section: Apoptosis and Its Equilibria With Stem Cell Recruitment In Tmentioning

confidence: 99%

Section: Apoptosis and Its Equilibria With Stem Cell Recruitment In Tmentioning

confidence: 99%

Section: Apoptosis and Its Equilibria With Stem Cell Recruitment In Tmentioning

confidence: 99%

“…Excess Pit-1 activates the Arf promoter (Pit-1+/p19Arf+, cyan merge). All these markers are nuclear (pink merge: TUNEL+Pit-1+p19Arf+DAPI) [95]. …”

Section: From Adult Stem To Committed and Differentiated Cells In The Apmentioning

confidence: 99%

See 2 more Smart Citations

Pituitary Cell Turnover: From Adult Stem Cell Recruitment through Differentiation to Death

et al. 2015

View full text Add to dashboard Cite

show abstract

“…When stimulated by GDNF, it behaved as as an oncogene able to activate intracellular signaling and cell survival. Instead, in the absence of GDNF, RET behaved as a tumor suppressor; caspase-mediated RET processing induced Pit-1 expression, that, in turn, caused p19Arf and p53 upregulation and apoptosis [46,49].…”

Section: Ret As a Tumor Suppressormentioning

confidence: 99%

RET: A Multi-Faceted Gene in Human Cancer

2012

View full text Add to dashboard Cite

Multiple Functional Effects of RET Kinase Domain Sequence Variants in Hirschsprung Disease

et al. 2012

View full text Add to dashboard Cite

The REarranged during Transfection (RET) gene encodes a receptor tyrosine kinase required for maturation of the enteric nervous system. RET sequence variants occur in the congenital abnormality Hirschsprung disease (HSCR), characterized by absence of ganglia in the intestinal tract. Although HSCR-RET variants are predicted to inactivate RET, the molecular mechanisms of these events are not well characterized. Using structure-based models of RET, we predicted the molecular consequences of 23 HSCR-associated missense variants and how they lead to receptor dysfunction. We validated our predictions in biochemical and cell-based assays to explore mutational effects on RET protein functions. We found a minority of HSCR-RET variants abrogated RET kinase function, while the remaining mutants were phosphorylated and transduced intracellular signals. HSCR-RET sequence variants also impacted on maturation, stability, and degradation of RET proteins. We showed that each variant conferred a unique combination of effects that together impaired RET protein activity. However, all tested variants impaired RET-mediated cellular functions, including cell transformation and migration. Our data indicate that the molecular mechanisms of impaired RET function in HSCR are highly variable. Although a subset of variants cause loss of RET kinase activity and downstream signaling, enzymatic inactivation is not the sole mechanism at play in HSCR.

show abstract

Direct promoter induction of p19Arf by Pit-1 explains the dependence receptor RET/Pit-1/p53-induced apoptosis in the pituitary somatotroph cells

Cited by 21 publications

References 65 publications

Pituitary Cell Turnover: From Adult Stem Cell Recruitment through Differentiation to Death

Pituitary Cell Turnover: From Adult Stem Cell Recruitment through Differentiation to Death

RET: A Multi-Faceted Gene in Human Cancer

Multiple Functional Effects of RET Kinase Domain Sequence Variants in Hirschsprung Disease

Contact Info

Product

Resources

About