There will be no sections the first week of class, but you should sign up for a section on the sheets posted in the lobby of Pacific Hall. Sections will begin the second week of classes. The term "molecular biology" also refers to the collection of tools used to carry out these studies. Advances in molecular biology have led to an understanding of human health and disease and also form the basis of recombinant DNA technology and the biotechnology industry.
By the end of the course, you should understand the molecular "machinery" that carry out cellular processes and how these processes are regulated. You should also understand the experimental science that has facilitated the understanding of these concepts and allows us to gain a more detailed understanding of cellular processes.
Finally, you will have a sense of the exciting new directions in molecular biology and the provocative and, as yet, unanswered questions that await us. Welcome to what I think will be a challenging and exciting foray into the molecular mechanisms underlying cellular function!
Readings from Lodish are noted and any additional reading will be announced in lecture and indicated on the course website. Please note that the indicated schedule and readings may be modified somewhat during the quarter, and any changes will be announced in lecture.
Lecture notes will be posted on the class website. However, these notes are not intended to replace lecture, and you will be responsible for information provided in lecture and assigned in the text. Reading--Reading assignments are noted on the schedule. Any additional reading will be announced in lecture and on the web site.
You are encouraged to read text material before lectures. You will note that at the end of each chapter, problems and lists of key concepts are given.
Additionally, the website for the text has supplemental material, including animations and figures from the text. You are encouraged to try solving these problems and making use of supplementary material before lecture.
Problem Solving--In addition to problems given at the end of the chapter, problem sets will be assigned weekly starting at the end of week 1. They will be posted on the website by Friday afternoon. You are encouraged to work these problems before section and to be prepared to discuss the answers during section. The exam questions will directly reflect the homework assignments. The thing that worries me about Warren is the writing requirement since my English isn't very good - how difficult is it to get an A?
Also, is there a foreign language requirement? I have quite a few AP credits, but I'm not sure if it would be a good idea to use them or retake the classes. Thanks for your help. If you think you would need more help, go to the professor's or TA's office hours. This will free up your time to take other classes in which you also have interest. With good time management, I'm sure you can balance all of your activities. If a quarter starts to become too demanding, just drop a class.
All Rights Reserved. Amino acids which diverge from the human sequence are indicated in black. Acta Physiol , , — evolution, whereas other bioactive peptides, such as pituitary compared with all other tissues, and that CgB PST or CST, have no homologous sequence in non- exhibits a more diffuse expression. In other non- mammalian CgAs Turquier et al.
Several pep- mammalian vertebrates, CgA, CgB and SgII expression tides that derive from the C terminus of CgB have also was detected in the brain, the pituitary, the adrenal been isolated and characterized see below.
However, gland and the intestine of chicken Salvi et al. The most Zhao et al. Overall, these studies highly conserved region in SgII is that encompassing SN showed that granins are also widely expressed in Anouar et al. The conservation of SN mammalian vertebrates Table 2 , although differences sequences in various vertebrate species was confirmed in their abundance within tissues may occur, in com- through polymerase chain reaction PCR cloning parison with mammals.
Leitner et al. Within the frog pituitary, CgA and SgII are present in both the distal and the neurointermediate lobes, whereas CgB only occurs in the pars distalis. Conversely, the levels species Mahata et al. The majority of of these transcripts are downregulated when the animals endocrine and neuroendocrine cells express at least one are placed on a white background.
Recently, Peinado member of this family of acidic proteins. Pituitary cells, et al. In the central and background-adapted animals, the two proteins could peripheral nervous systems, granins are widely play rather different roles in the regulated secretory expressed with highest concentrations occurring in cer- pathway in melanotrophs.
Thus, CgA expression and tain brain structures such as the hypothalamus, hippo- processing may be related to hormone storage in campus, amygdala and cerebellum Mahata et al. The relative cessing could be part of the active hormonal release abundance of granins varies in a tissue- and species- from melanotrophs. For instance, SgII is highly expressed in gonadotrophs compared with other pituitary cells or in Biological roles glucagon-producing alpha cells compared with the other pancreatic endocrine cell types Fischer-Colbrie et al.
Since their discovery, intense investigations have been Thus, northern blot, reverse The first chromogranin-derived peptide to be discovered transcription-PCR and in situ hybridization analyses was the CgA peptide PST, which was initially identified have been performed to provide the first overall in porcine pancreas Tatemoto et al. PST exerts mapping of granins in a non-mammalian species multiple, potentially dysglycaemic actions, including Anouar et al.
It was found that SgII is more highly expressed in pancreatic b-cells Tatemoto et al. In humans, PST affects both carbohydrate effect on chromaffin cells in vivo. One of stressors, suggesting that a reduction in CST may the three naturally occurring variants GlySer of increase the risk of hypertension.
The intermediary metabolism and disease, and suggest that naturally occurring human variants of CST GlySer, qualitative hereditary alterations in the primary struc- ProLeu and ArgGln displayed differential ture of PST may give rise to inter-individual differences potencies towards inhibition of nicotinic cholinergic in glucose disposition.
Several other CgA-derived pep- agonist-evoked catecholamine secretion from sympatho- tides have been described after PST discovery. In vivo, human Helle , Aardal et al. VS also act as evolved rapidly to meet the physiological demands negative inotropic agents in lower vertebrate hearts specific to mammals. Corti et al. One of these was named secretolytin as it Gallo et al. VS-derived peptides have also been shown exhibits antibacterial activity Strub et al.
The sequence of secretolytin is highly preserved in a , to trigger neuronal apoptosis Taupenot et al. Other peptides rat Ghia et al. HQ Wang et al. The CST peptide was initially identified as the most , Laslop et al. Polymorphisms in the CgB locus have been et al. Subsequently, CST was reported to be associated with schizophrenic individuals found to act as a potent vasodilator in vivo in rat by Zhang et al.
Neurological pathologies like stimulating the release of histamine Kennedy et al. Such release of histamine by CST was also poral lobe epilepsy Mahata et al. SN is also detected in the cerebrospinal antimicrobial peptide Briolat et al.
The plasma fluid Kirchmair et al. Subjects with systems. SN releases dopamine from the rat striatum such a family history demonstrate increased epinephrine Saria et al.
It role in the generation of secretory vesicles. In addition, increases monolayer permeability in human coronary stored SgII could be released in a regulated manner from artery endothelial cells Yan et al. SN also acts as transfected, constitutively secreting cells Beuret et al. Although there is currently some controversy as vascular endothelial growth factor Kirchmair et al. To gain a ischaemia or in solid tumours Fischer-Colbrie et al.
So far, binding sites for SN were generated which displayed decreased chromaffin have been characterized only on human monocytes granule size and number, elevated blood pressure, loss Kong et al. Flanking SN at its C-terminus, et al.
The human orthologue CHGA transgenic the peptide EM66 which occurs in all species studied to mice were created in this null background by bacterial date, including the frog R. The human gene Hadjadje et al. You, restored the blood pressure to normalcy in these mice, M. Anouar, unpublished suggesting a definitive role for CHGA in autonomic observations , is also of potential interest. It has recently control of circulation.
The number of DCGs formed fasting Boutahricht et al. The data from CgA knockout and CgA antisense transgenic mice indicate an essential role Intracellular functions of CgA in regulating chromaffin DCG biogenesis and Because granins are localized in secretory granules of catecholamine storage in vivo.
Using a different CgA virtually all neuroendocrine cells and because several null mice strain, Hendy et al. Knockout models are currently lacking secretory vesicles in neuroendocrine cells. Inhibition of for other granins in order to demonstrate their involve- the expression of CgA in PC12 cells leads to a marked ment in intracellular events associated with hormone decrease in secretory granule formation and to impair- and neurotransmitter release.
Recently, Interestingly, expression of frog CgA also induced Courel et al. Other studies revealed intracellular role in secretory granule formation in that CgB Huh et al. This finding indicates that the are also able to induce the formation of secretory high content of acidic amino acids in frog CgA, alone or granule-like structures in non-neuroendocrine cells in combination with the conserved N- and C-terminal which are normally devoid of a regulated pathway of regions, is probably sufficient to confer aggregating secretion, suggesting that granins may play a crucial properties to this granin.
Recently, an interaction between SgIII and carboxypep- tidase E has also been demonstrated and shown to facilitate prohormone sorting within secretory granules in endocrine cells Hosaka et al. For N instance, it has been shown that CgA and CgB are involved in intracellular calcium mobilization as these granins bind to the inositol 1,4,5-trisphosphate IP3 receptor that is present on the membranes of secretory granules and facilitate calcium release in response to IP3 Yoo et al. It has also been shown that a fraction of immunoreactive CgB in PC12 cells can localize to the nucleus and that the granin is able to stimulate or repress the transcription of different genes, including transcription factors, when overexpressed in neuroblas- toma cells Yoo et al.
Using antibodies directed against specific peptides derived from CgA, we have observed immunostaining of the nucleus in PC12 cells Montero-Hadjadje et al. Cryofixed cells were processed for electron microscopy. Recently, it has been shown that CgA may a COS7 cells were transfected with the empty eukaryotic protect secretory granule proteins from degradation expression vector pIRES used as a control. Arrows indicate newly sion of protease nexin-1, a serine protease inhibitor formed secretory granules.
N, nucleus. Finally, a clear intracellular function has been established for the granin-like protein high proportion of acidic amino acids in all species 7B2 which binds and activates PC2 through two studied to date, this structural feature may well repre- domains that have been highly conserved in various sent a critical, if not the sole, requirement for the species, including the toad X. A motif consisting Most of the functional characteristics of 7B2 of the N-terminal disulfide loop domain is involved in have been deduced from initial studies performed in the association of CgB with the membrane in the trans- xenopus melanotrope cells in which this protein is also Golgi network TGN and sorting of CgB to the regulated in concert with POMC during background regulated secretory pathway in PC12 cells Chanat colour adaptation Martens et al.
More recently, et al. Although this loop the introduction of 7B2-knockout mice models confirms structure is also present in CgA, it does not appear to be and extends these early studies Peinado et al. Instead, Concluding remarks a different domain CgA of mature CgA appears to be necessary, although not sufficient, for trafficking The function of the neuroendocrine granin proteins has of this protein to the regulated secretory pathway.
Although their required for inhibition of parathyroid hormone secretion. An intracellular role J. Molecular cloning of frog secre- togranin II reveals the occurrence of several highly conserved of granins has received strong support during the last potential regulatory peptides. FEBS Lett , — Identification of a intracellular intervention of these proteins in hormone novel secretogranin II-derived peptide SgII in storage and release.
Besides, the role of granins as adult and fetal human adrenal glands using antibodies raised precursors to neuropeptides and hormones is an attrac- against the human recombinant peptide. J Clin Endocrinol tive notion that still needs to be substantiated.
Several Metab 83, — Primary structure of peptides have remained elusive. The primary existence of specific receptors and the effects of some of structure of bovine chromogranin A: a representative of a these peptides in vivo should be clarified. Characteriza- class of acidic secretory proteins common to a variety of tion of granins and granin-derived peptides in phyloge- peptidergic cells. EMBO J 5, — The primary structure of human ical contribution of these proteins in homeostatic secretogranin I chromogranin B : comparison with chro- regulations.
EMBO J 6, — Benjannet, S. GAWK, a novel human pituitary polypeptide: isolation, immunocytochemi- None. J Biol Chem , — Bitsche, M. First localization and biochemical identifi- References cation of chromogranin B- and secretoneurin-like Aardal, S. Regul Pept , 97— Regul Pept 41, 9— Smith, A. Secretion of a chromaffin granule protein, Aardal, S. Vasostatins, comprising the N-terminal stimulation.
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Bellafgih, S. Acta Physiol , , — and immunohistochemical localisation of the secretogranin cytokine secretoneurin via an HIF-1alpha- and basic FGF- II-derived peptide EM66 in the hypothalamus of the jerboa dependent pathway in muscle cells.
Jaculus orientalis : modulation by food deprivation. Eiden, LE. Is chromogranin a prohormone? Nature , J Neuroendocrinol 17, — Briolat, J. Chasserot-Golaz, S. New antimicrobial activity for the into chromogranin B and into a proteoglycan. J Neurochem catecholamine release-inhibitory peptide from chromogranin 45, — Cell Mol Life Sci 62, — Falkensammer, G. Cell-free and cellular synthesis of chromogranin A Recombinant N-terminal fragments of chromogranin- and B of bovine adrenal medulla.
Neuroscience 14, — A modulate cardiac function of the Langendorff-perfused rat Ferrero, E. Basic Res Cardiol , 43— Colombo, B. Chanat, E. Milieu-induced, selective Chromogranin A protects vessels against tumor aggregation of regulated secretory proteins in the trans-Golgi necrosis factor alpha-induced vascular leakage. J Cell Biol , — Fischer-Colbrie, R.
Sequence analysis, tissue distribution and togranin I in the trans-Golgi network causes its missorting to regulation by cell depolarization, and second messengers of the constitutive secretory pathways. EMBO J 12, — J Biol Conlon, J. Isolation Chem , — Secre- cessing of chromogranin A and chromogranin B from human togranin II: molecular properties, regulation of biosynthesis pheochromocytoma tissue.
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