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Sometimes it's neither the hormones nor the genes

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Sometimes it's neither the hormones nor the genes
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  TRENDSin Endocrinology & Metabolism Vol.12 No.8 October 2001 http://tem.trends.com 1043-2760/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S1043-2760(01)00470-2 333 Research Update Research News In addition to transcriptional andtranslational regulatory processes,targeting of cellular proteins forproteosome-mediated degradationprovides an important regulatory step bywhich cell function can be modulated.Now a physicochemical factor,osmoticstress,has been shown to affectpolyubiquitination of aquaporin-1.Thismodel system suggests the need forendocrine studies to consider non-genomicand non-receptor-mediated processes thatalter cell function in general and that mighteven contribute to the appearance andprogression of disease. Endocrinologists are quite familiar withthe concept of transcriptional regulation of cell protein synthesis. Most of thehormones we know and love include,among their extensive repertoire of actions, both up- and downregulation of the transcription of a variety of cellproteins. Arecent paper by Leitch  et al. 1 should be of interest to endocrinologistsbecause it makes two important pointsthat are sometimes overlooked in our field.Namely, (1) physicochemical factors, suchas osmolality, can have profound effects onthe regulation of cell protein expressionand metabolic effects independently of hormone–receptor interaction-mediatedevents (i.e. it is not always hormones thatare the key players); and (2) theexpression of cell proteins can sometimesbe influenced by post-transcriptionalevents as much as, or even more than, bytranscriptional regulation (i.e. it is notalways turning genes on and off that ismost important either).Leitch  et al. studied the expression of aquaporin-1 (AQP1), which is theubiquitous water channel discovered byPeter Agre in 1991. Although water candiffuse through lipid bilayers, itspermeability coefficient is quite low;insertion of water channels into the cellmembrane is necessary to achieve morerapid facilitated transport of water acrosscell membranes. It makes sense thatunder conditions of osmotic stress, theexpression of AQP1 would be increased toallow more rapid equilibration of waterbetween the intracellular andextracellular fluid compartments, and thishas beenfound to be the case in culturedcells. The mechanism of this increasedexpression does not, however, appear to bemediated solely via transcriptionalregulation. Hyperosmolality caused aseveral-fold prolongation of the half-life of  AQP1 in cultured BALB/c fibroblasts,from ~50% of baseline protein levelswithin four hours under isoosmolarconditions to ~80% of baseline proteinlevels under hyperosmolar conditions(Fig. 1). Thus, hyperosmolality increasedthe stability of AQP1, in essence greatlymagnifying any effects produced byincreased mRNAtranscription.The mechanism through which thisoccurs is of general biochemical interest.Proteins in cells are often targeted fordegradation by a post-translationalmechanism involving polyubiquitinationof the protein, which then selects it forprocessing by 26S proteasomes 2 . Theauthors of this paper present strong evidence that AQP1 is also degraded by this mechanism: (1) proteasomeinhibitors increased AQP1 expression incultured fibroblasts; (2) ubiquitinimmunoreactivity was identified bywestern blotting of immunoprecipitates of  AQP1; (3) ubiquitination was decreased infibroblasts cultured under hyperosmolarconditions; and (4) the half-life of [ 35 S]methionine-labeled AQP1 wasmarkedly prolonged in fibroblastscultured in hyperosmolar (500 mOsm kg  −1 H 2 O) medium. What is particularlyremarkable about these findings is thatthe decrease in ubiquitination withresultant increased stability of AQP1occurred during severe osmotic stress, acondition generally associated withreduced protein synthesis; this suggests avery specific and highly regulatedmechanism for targeting selected proteinsfor polyubiquitination and degradation.Thus, AQP1 is now known to be among those proteins, including many cytosolicand membrane receptors, that aredegraded through the polyubiquitination–proteasome pathway. This is a nice story,but so what?Recognition of the involvement of thispathway for degradation of cytosolic andmembrane proteins has severalimplications. First, it emphasizes theimportance of considering physicochemicalfactors when interpreting cell function.Physiologists studying the regulation of arginine vasopressin (AVP) secretion fromthe neurohypophysis have long known theimportance of plasma osmolality as theprimary regulator of neurohypophysealsecretion of this hormone. Studies such asthose of Leitch  et al. show that it is not justthe neurohypophysis that can respond toosmotic changes; AQP1 now joins asizeable list of cell proteins whoseexpression is influenced by changes inambient osmolality as a defensemechanism against osmotic stresses.Consequently, both in vitro and in vivo studies of hormone effects should notignore such physicochemical factors either.Second, these studies highlight theimportance of post-transcriptionalmechanisms in the regulation of theexpression and biological activity of cellproteins. Such processes have too oftenbeen overlooked as mechanisms toenhance and amplify the effects of hormones at their receptors. However,protein degradation represents just one of many post-transcriptional mechanismsthat can potentially affect the synthesis Sometimes it’s neither the hormones nor the genes Joseph G. Verbalis TRENDS in Endocrinology & Metabolism 02468120100806040200    A   Q   P   1   (   %    b  a  s  e   l   i  n  e   ) Time (h) Fig.1. Aquaporin-1 (AQP1) protein stability in fibroblastscultured under isotonic (closed symbols) and hypertonic(open symbols) conditions, expressed as a percent ofbaseline levels after different incubation times.Reproduced, with permission, from Ref. 1.  and stability of cell proteins. For example,recent studies of expression of theangiotensin AT 1a receptor have implicatedestrogen-mediated regulation of proteintranslation via changes in the activity of cytosolic binding proteins that correlatewith changes in receptor binding levelsindependently of changes in mRNA expression 3 . Thus, we should not be somyopic as to equate only mRNAlevelswith the regulation of cell proteinexpression.Third, these and related studies raisethe possibility that some disease statesmight be produced or exacerbated byalterations in either theubiquitination–proteasome system, or bymutations in proteins that alter theirability to be ubiquinated. For example, the β -subunit of the epithelial Na + channel(ENaC), one of the targets of aldosteroneactions in the distal nephron, is mutatedin cases of Liddle’s syndrome, and one of the effects of the mutations could be toalter ubiquitination and proteindegradation of the ENaC subunits 1 .Finally, as already alluded to, one of thebest-known neuroendocrine systems, theneurohypophysis, is tightly regulated byphysiological changes in plasmaosmolality. We know that the neurons thatsynthesize AVPand oxytocin upregulatethe synthesis of these peptides underconditions of hyperosmolality, andconversely, they downregulate synthesisunder hypoosmolar conditions 4 . Morerecently, these magnocellular neuronshave been shown to manifest coordinatedglobal changes in the synthesis of a widevariety of cell proteins in response tohyper- and hypoosmolar conditions 5 . Themagnitude of these osmotic effects on cellsynthetic activity is such that themagnocellular neurons of the supraopticnucleus increase in size by 50–60% during chronic hyperosmolality, and shrink insize by 30–40% during chronichypoosmolality 6 . It would be unusual if such dramatic changes in cell activityoccurred solely at the level of transcriptional regulation, andmechanisms such as regulatedpolyubiquitination are probably involvedin global regulation of neuroendocrine cellfunction. This endocrine system thereforerepresents an ideal model for studying both transcriptional and post-transcriptional osmotic regulation of cellprotein expression and activity.Thus, advances such as those reportedby Leitch  et al. shed light on much morethan simply the regulation of AQP1expression in fibroblasts. They serve toremind us of the possibility of importantpost-transcriptional controls of otherproteins in endocrine systems, they alertus to the possibility of disease states thatmight result from alterations in cellprotein processing, and they are of direct relevance to the activity of a major,but oft forgotten neuroendocrine system,the neurohypophysis. So this very nicestory is, indeed, of relevance toendocrinologists, as are most basicadvances in cell biology. References 1Leitch, V.V.  et al. (2001) Altered ubiquitinationand stability of aquaporin-1 in hypertonic stress.  Proc. Natl. Acad. Sci. U. S. A. 98, 2894–28982Ciechanover, A.  et al. (2000) The ubiquitin-mediated proteolytic pathway: mode of action andclinical implications.  J. Cell Biochem. (Suppl.)34,40–513Krishnamurthi, K.  et al. (1999) Estrogenregulates angiotensin AT1 receptor expression viacytosolic proteins that bind to the 5 ′ leadersequence of the receptor mRNA.  Endocrinology 140, 5435–54384Robinson, A.G.  et al. (1990) Hyponatremia in ratsinduces downregulation of vasopressin synthesis.  J. Clin. Invest. 86, 1023–10295Glasgow, E.  et al. (2000) Gene expression in therat supraoptic nucleus induced by chronichyperosmolality versus hyposmolality.  Am. J. Physiol. Regul. Integr. Comp. Physiol. 279,R1239–R12506Zhang, B.  et al. 2001 Chronic hypoosmolalityinduces a selective decrease in magnocellularneurone soma and nuclear size in the rathypothalamic supraoptic nucleus.  J.Neuroendocrinol. 13, 29–36 Joseph G.Verbalis Georgetown University, Washington,DC20007, USA.e-mail: verbalis@georgetown.edu TRENDSin Endocrinology & Metabolism Vol.12 No.8 October 2001 http://tem.trends.com 1043-2760/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S1043-2760(01)00468-4 334 Research Update A breakthrough in the study of cancer anorexia Willis K. Samson and Meghan M. Taylor The control of appetite and satiety hasenjoyed a renewed focus largely because of the discovery of several peptidehormones that transmit important signals to feeding centers in brain.Stimulatory (orexigenic) and inhibitory(anorexigenic) neuropeptide systems havebeen identified and the importance ofhormonal input from the periphery hasbeen established.However,the chemicalmediators of cancer-induced anorexia have yet to be clearly identified.Now,usinga selective receptor antagonist,the crucialrole of the endogenous α -melanocyte-stimulating hormone–melanocortinreceptor system in brain has beenidentified to be the point of convergencefor the cytokine-mediated anorexia andwasting. Numerous hormones and centrallyproduced neuropeptides have beenidentified recently to be potent regulatorsof appetite and food intake in experimentalanimals. Central to most theories of appetite regulation 1 is the hormone leptin,identified 2 as the adipocyte-derivedanorexic factor that signals bodycomposition to brain. Leptin acts in brainto control the production and/or release of the anorexigenic neuropeptide α -melanocyte stimulating hormone ( α -MSH), the product of hypothalamicproopiomelanocortin (POMC) genetranscription/translation. Leptin also actsin brain to inhibit the release of severalorexigenic peptides, including orexin,neuropeptide Y (NPY) and agouti gene-related peptide (AGRP). Alongstanding question has been the roles of thesecirculating and brain-derived peptides incancer-induced anorexia.Proinflammatory cytokines, which areelevated in malignancy, were thought to bethe primary signals to the endogenousorexigenic and anorexigenic pathwaysinitiating the cachexia and wasting observed; however, a conclusive linkbetween these cytokines and cancer-induced anorexia has not been established.Now, Wisse  et al. 3 have provided thatlink and the cellular basis of cancer-induced anorexia is clearer.Proinflammatory cytokines, such asinterleukin-1 β (IL-1 β ), interleukin-6(IL-6) and tumor necrosis factor- α (TNF- α ), were hypothesized by theseauthors to stimulate central POMC
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